JP2016165721A - Spray drying technique - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a spray drying method which can perform control of a dried product when a consistent distribution in size is desired.SOLUTION: An article containing one or more channels or microfluidic channels is used to mix one or more fluids prior to spray drying. The mixing may occur immediately before the fluids are expelled through a nozzle or another opening into a drying region of a spray dryer. For example, a first fluid is exposed to a second fluid, then the fluids are exposed to air or another gas before being expelled through the nozzle. In a certain case, the first fluid may contain a dissolved species that may precipitate upon exposure to the second fluid; and such precipitation may occur immediately before expulsion through the nozzle or the other opening, thereby resulting in controlled precipitation as a part of the spray drying process.SELECTED DRAWING: Figure 1

Description

RELATED TECHNOLOGY This application was filed on Dec. 21, 2010, and filed on May 11, 2011, and US Provisional Patent Application No. 61 / 425,415 entitled “Spray Drying Techniques” by Abate et al. Claims the benefit of US Provisional Patent Application No. 61 / 485,026 of the title “Spray Drying Techniques” by Abate et al. Each of these is hereby incorporated by reference.

The present invention relates generally to microfluidics, and spray drying and other drying techniques.

  Spray drying is a commonly used technique for drying materials, many of which are food (eg, milk powder, coffee, tea, eggs, cereals, spices, flavorings, etc.), pharmaceutical compounds (eg, antibiotics). Substances, medical ingredients, drugs, additives, etc.), industrial compounds (eg paint pigments, ceramic materials, catalysts, etc.), etc. are used in various applications such as spray drying. In spray drying, the material to be dried is typically discharged from the nozzle into an area to be dried and / or heated to dry the material. This material is often a liquid, but other materials may also be dried, such as, for example, a wet solid material or a partially melted solid material. The area used for drying may contain air or nitrogen and in some cases is heated. The material is typically broken into smaller pieces, for example by using a nozzle, increasing the exposed surface area, thereby reducing the drying time of the material. However, such drying techniques can be difficult to control if, for example, a consistent size distribution is desired for the dried product.

  The present invention relates generally to microfluidics, and spray drying and other drying techniques. The subject matter of the present invention includes, in some cases, interrelated products, alternative solutions to a particular problem, and / or multiple different uses of one or more systems and / or articles.

  In one aspect, the present invention is generally directed to a spray dryer. In one set of embodiments, the spray dryer includes a first microfluidic channel having an opening as a nozzle and a second microfluidic channel that intersects the first microfluidic channel at an intersection upstream of the nozzle. An article comprising In some cases, the spray dryer may further comprise a drying area that receives the output from the nozzle.

  According to another set of embodiments, the spray dryer may include an article comprising one or more microfluidic channels having both an average cross-sectional dimension of less than about 1 mm and an overall length of at least about 10 mm. The spray dryer may also include a drying area that receives the output from the nozzle. In some cases, at least one of the microfluidic channels has an opening in the article that acts as a nozzle.

  The spray dryer includes, in yet another set of embodiments, an article comprising a fluid channel having a cross-sectional aspect ratio of at least about 3: 1 and a drying region that receives output from the nozzle. The spray dryer may further include a fluid channel having an opening that acts as a nozzle.

  In yet another set of embodiments, the spray dryer includes a fluid channel containing a first liquid and a second liquid, an outlet of the fluid channel acting as a nozzle, and a drying region that receives the output from the nozzle. Prepare. In certain embodiments, the second liquid surrounds the first liquid so that the first liquid does not contact the walls of the fluid channel closest to the outlet.

  In another set of embodiments, the spray dryer includes a first fluid channel having an opening that acts as a nozzle, and a second fluid channel that intersects the first fluid channel at an intersection upstream of the nozzle. A third fluid channel that intersects the first fluid channel at an intersection upstream of the nozzle. The spray dryer may further include a drying area that receives the output from the nozzle.

  The spray dryer, according to yet another set of embodiments, includes an article comprising an elastomeric polymer, the article comprising a fluid channel having an opening that acts as a nozzle, and a drying region that receives the output from the nozzle. Is provided.

  In yet another set of embodiments, the spray dryer includes a mechanically deformable article comprising a fluid channel having an opening that acts as a nozzle and a drying region that receives the output from the nozzle.

  According to yet another set of embodiments, the spray dryer is a dryer that receives at least 10 articles each having a fluid channel having an opening that acts as a nozzle and the output from the nozzles of the at least 10 articles. And may include a region. In yet another set of embodiments, the spray dryer comprises an article comprising at least 10 fluid channels each having an opening that acts as a nozzle, and a drying region that receives the output from each of the at least 10 nozzles. Including. According to yet another set of embodiments, the spray dryer comprises at least 10 articles, each article receiving an output from the nozzle with an article comprising a fluid channel having an opening that acts as a nozzle. A drying area.

  The spray dryer, in another set of embodiments, includes a pseudo two-dimensional article comprising a fluid channel having an opening that acts as a nozzle and a drying region that receives the output from the nozzle.

  In another aspect, the present invention is generally directed to a method of spray drying a fluid or liquid, for example. The method, according to one set of embodiments, provides an operation of providing a first liquid that includes a species dissolved in the first liquid, and the first liquid in the fluid channel for a period of about 30 seconds or less. Exposing the liquid to a second liquid and spraying the first liquid and the second liquid onto a dry area outside the fluid channel. In certain embodiments, the species does not substantially dissolve in the second liquid.

  In another set of embodiments, the method includes exposing the first liquid to the second liquid in the microfluidic channel, and bringing the first and second liquids outside the microfluidic channel. And discharging to a certain drying area.

  In yet another set of embodiments, the method provides a channel including a liquid delimited by a first bolus upstream of the liquid and delimited by a second bolus downstream of the liquid. And an operation of discharging the liquid to a drying area outside the fluid channel.

  In another set of embodiments, the method includes an operation of providing a first liquid that includes a species dissolved in the first liquid, and the first liquid in the fluid channel for a period of about 30 seconds or less. An operation of exposing the seed to a second liquid that cannot substantially dissolve, and an operation of spraying the first liquid and the second liquid onto a dry region outside the fluid channel. The method, according to yet another set of embodiments, provides an operation of providing a first liquid comprising a species dissolved in the first liquid and an operation of precipitating the species from the first liquid in a fluid channel. And spraying the first liquid and the seeds onto a dry area outside the fluid channel.

  The method, in yet another set of embodiments, includes providing a double emulsion to the microfluidic channel and spraying the double emulsion to a dry area outside the microfluidic channel.

  In yet another set of embodiments, the method is an operation of passing a liquid through a microfluidic channel, wherein the liquid flowing through the fluid channel has a Reynolds number of at least about 1; And the operation of discharging to an outside drying area.

  The method, according to another set of embodiments, exposes the first liquid to the second liquid and directs the first liquid and the second liquid to a dry region outside the microfluidic channel. Draining to obtain the product and collecting the product in a collection chamber having a volume of less than about 20 ml.

  In another aspect, the invention encompasses a method of making one or more of the embodiments described herein (eg, spray drying and other drying techniques involving microfluidics). In yet another aspect, the invention encompasses methods using one or more of the embodiments described herein (eg, spray drying and other drying techniques involving microfluidics).

  Other advantages and novel features of the invention will become apparent from the following detailed description of various non-limiting embodiments of the invention when considered in conjunction with the accompanying drawings. In the event of a conflicting and / or inconsistent disclosure in this specification and in a document incorporated by reference, the content of this specification should be followed. If two or more documents incorporated by reference have conflicting and / or inconsistent disclosures with respect to each other, the effective date should follow the later document.

  Non-limiting embodiments of the present invention will now be described by way of example with reference to the accompanying drawings, which are schematic and are not intended to be drawn to scale. In the drawings, each identical or nearly identical component illustrated is typically represented by a single numeral. For the sake of clarity, not all elements are numbered in each figure, and those portions that are not necessary for those skilled in the art to understand the present invention are described in each embodiment of the present invention. Not all elements are shown.

1A-1B illustrate various microfluidic devices according to certain embodiments of the invention. 2A-2C illustrate a microfluidic device that includes a pressurized fluid in another embodiment of the present invention. 3A-3D show the spray profiles of certain embodiments of the present invention. 4A-4E illustrate the effect of solvent in yet another embodiment of the invention. 4A-4E illustrate the effect of solvent in yet another embodiment of the invention. 4A-4E illustrate the effect of solvent in yet another embodiment of the invention. 5A-5E illustrate the effects of spatial sampling in yet another embodiment of the present invention. 5A-5E illustrate the effects of spatial sampling in yet another embodiment of the present invention. 6A-6F show inhibition of crystallization in yet another embodiment of the invention. 6A-6F show inhibition of crystallization in yet another embodiment of the invention. Figures 7A-7D show comparable results using a conventional spray dryer, in accordance with certain embodiments of the present invention. Figures 7A-7D show comparable results using a conventional spray dryer, in accordance with certain embodiments of the present invention. FIG. 8 is a schematic view of a spray dryer according to still another embodiment of the present invention. 9A-9C illustrate another embodiment of the present invention that reduces or is not soiled by the precipitating agent.

  The present invention relates generally to microfluidics, and spray drying and other drying techniques. In one aspect, an article that includes one or more channels or microfluidic channels is used to mix one or more fluids prior to spray drying. This mixing may take place immediately before the fluid is discharged to the drying area of the spray dryer through a nozzle or other opening. In one set of embodiments, for example, the first fluid is exposed to the second fluid, and then the fluid is exposed to air or other gas before being discharged from the nozzle. In certain cases, the first fluid may contain dissolved species, which may precipitate when exposed to the second fluid, such precipitates may be produced by a nozzle or other It may occur just prior to draining through the opening, thereby causing controlled precipitation as part of the spray drying process.

  Accordingly, in certain aspects, the present invention is generally directed to a spray dryer. In a spray dryer, the fluid (typically a liquid) is discharged to a drying area to at least partially dry the fluid. In some cases, drying the fluid produces particles or solids. The drying zone may include heated gas and / or reduced humidity gas to facilitate drying. Examples of gases that may be used for drying include, but are not limited to, air or nitrogen. According to certain embodiments, fluid may be discharged through a nozzle or other opening into the drying area, which can be used to form droplets from the fluid. Droplets increase the contact area between the fluid and the gas surrounding the fluid and increase the drying rate. In some cases, the fluid may be combined with other fluids when directed through the nozzle, eg, the fluid may be combined with air or other gas to form droplets from the fluid. Spray drying is used in a variety of applications where drying is desired. For example, spray drying may be used to dry the heat sensitive or pyrolyzable material and / or the fluid may be dried at a controlled rate. In some cases, spray drying may be used to produce relatively uniform particles, for example due to drying the fluid at a controlled rate. Other non-limiting examples of materials and applications suitable for spray drying include those described above and those described herein.

  In certain embodiments, the present invention is directed to a spray dryer that uses one or more articles comprising various channels and prepares the fluid prior to or as part of the spray drying process. Some or all of the channels may be microfluidic channels. The channel may be used to drain the fluid to a drying area in the spray dryer, in some cases, for example, to add or mix the fluid, to drop seeds in the fluid to precipitate Alternatively, additional channels may be connected to the channel, such as to manipulate other species. These various non-limiting examples are discussed below.

  A non-limiting example of such a spray dryer will now be discussed with reference to FIG. In this figure, a fluid system 10 is shown. In certain embodiments, some or all of the channels shown in the fluid system 10 may be microfluidic channels, eg, microfluidic channels as described herein. The fluid system 10 in this example comprises a nozzle 12 located at the distal end of the first channel 20, but in other embodiments other openings (eg, openings on the sides of the channel) as well. Can be used. In this illustration, the first channel 20 is generally straight, but in other embodiments, the first channel 20 can be of various other geometries, such as any number of bends, zigzags, valves, etc. Or other channel elements may be present as part of the first channel 20. Fluid entering the first channel 20 enters from the first fluid source 25. The first fluid source 25 may be connected to a reservoir, pump, syringe, pipette, or another source of suitable liquid. The fluid may then be discharged through the nozzle 12 after passing through the first channel 20 (or, in some cases, a portion of the channel). The fluid may then be flowed to the drying zone 15 where it may be dried, for example, by exposure to a heated and / or reduced humidity gas.

  Further, FIG. 1 shows a second channel 30 and a third channel 32, each connected to a second fluid source 35. The second fluid originating from the second fluid source 35 may be the same as or different from the first fluid originating from the first fluid source 25. In this example, the second channel 30 and the third channel 32 intersect each other at a right angle with the first channel 20 at the same junction 23, and the second channel 30 and the third channel 32. Are in contact with the first channel 20 facing each other. In this example, the second channel 30 and the third channel 32 each suitably move around the first fluid source 25 from the second fluid source 35 in order to reach the fluid channel 20 at the junction 23. A route has been established. Although two channels are shown here, this is only an example, and in other embodiments, there may be other numbers of channels between the second fluid source 35 and the first channel 20. . For example, there can be 1 channel, 3 channels, 4 channels, 5 channels, 10 channels, and the like. In addition, in some cases, if more than one channel is present, the channels need not all intersect the first channel 20 at a common intersection.

  Using such a configuration, for example, the first fluid exiting from the first fluid source 25 and the second fluid exiting from the second fluid source 35 are joined at the junction 23 or downstream from the junction 23. They may be brought into contact with each other. The first fluid and the second fluid may be miscible or immiscible. For example, if the first fluid and the second fluid are immiscible, the first fluid may form droplets in the second fluid. Droplet formation can be controlled, for example, by controlling the nature of the fluid, the flow rate of fluid entering the junction 23, and the like. As another example, the first fluid and the second fluid may be at least partially miscible with each other. For example, the first fluid may include a species dissolved in the first fluid, which species is not soluble (or not as soluble) to the second fluid. For example, the species may be a species that is not substantially soluble in the second liquid, and as a specific example, the solubility of the species is at least an order of magnitude 2 greater than the solubility of the species in the first liquid. It may be smaller by 3 digits, 4 digits, or 5 digits (a power of 10). Subsequent exposure of the species to the second fluid starting from the junction 23 causes at least a portion of the species to begin to settle, for example, within the first channel 20, and is carried downstream as a solid precipitant toward the nozzle 12. obtain.

  In addition, FIG. 1 shows a third fluid source 45, which is connected to a fourth channel 40 and a fifth channel 42. The fourth channel 40 and the fifth channel 42 each intersect the first channel 20 at a junction 43, and in some embodiments, the junction 43 may be upstream of the junction 23 and downstream. There may be. At the junction 43, the fourth channel 40 and the fifth channel 42 intersect the first channel 20 at right angles and facing each other. For example, the fluid source 45 may be used to deliver a third fluid, which is the first channel just before the fluid in the first channel 20 exits through the nozzle 12. Delivered to 20. As a specific non-limiting example, a third fluid is used to break up other fluids in the first channel 20 to form individual or separate droplets, then for drying Separate droplets may be discharged from the first channel 20 to the drying region 15.

  The fourth channel 40 and the fifth channel 42 may be appropriately routed around other elements of the fluid system 10 to reach the junction 43 from the third fluid source 45. This example shows only two channels, but is for illustrative purposes only, and in other embodiments, other numbers of channels between the third fluid source 45 and the first channel 20. There may be (eg 1 channel, 3 channels, 4 channels, 5 channels, 10 channels, etc.). In addition, in some cases, if more than one channel is present, the channels need not all intersect the first channel 20 at a common intersection.

  Accordingly, various aspects of the present invention are directed to a spray dryer that uses one or more channels, such as microfluidic channels, to prepare a fluid before being discharged to a suitable drying area. The drying area may be open (eg, open to the atmosphere) or closed (eg, partially or fully surrounded by a drying chamber through which fluid is exhausted). For example, the drying chamber may contain at least partially a drying gas suitable for drying glass, plastic, or fluid discharged to the drying area, or any other suitable that can be used to enclose. It may be formed from a material. The drying gas may be air, nitrogen, carbon dioxide, argon, or other suitable gas. In certain embodiments, the gas is selected to be relatively inert or non-reactive with respect to the fluid being exhausted. However, in other embodiments, the gas may react with one or more of the fluids being exhausted. The drying gas can also be dehumidified using various techniques such as refrigeration or condensation cycles, electrical methods (eg Peltier heat pumps), desiccants (eg phosphorus pentoxide) or hygroscopic materials. In certain embodiments, the relative humidity in the dry zone is about 50% or less, about 40% or less, about 35% or less, about 30% or less, about 25% or less, about 20% or less, about 15% or less, about 10%. % Or less, or about 5% or less. Other techniques for controlling the relative humidity of an area will be known to those skilled in the art.

  In some cases, the drying area is heated, for example, using one or more heaters. The temperature of the drying zone can be, for example, in such a way that the drained fluid can be partially or fully dried (depending on the application), in some cases not causing inconvenient degradation or being drained. Can be selected so as not to react with the fluid. For example, using a heater, the drying zone is at least about 30 ° C, at least about 40 ° C, at least about 60 ° C, at least about 80 ° C, at least about 100 ° C, at least about 125 ° C, at least about 150 ° C, at least about 200 ° C, at least It may be heated to a temperature such as about 300 ° C., at least about 400 ° C., at least about 500 ° C. Any suitable method may be used to heat the drying area. For example, the dry area may be heated using induction heating, fuel combustion, exposure to radiation (eg, infrared), chemical reactions, and the like.

  The spray dryer may also include an article with one or more channels (eg, microfluidic channels). The article may be formed, for example, from polymeric, flexible and / or elastomeric polymers and / or other materials (eg, silicone polymers such as polydimethylsiloxane (“PDMS”)). In certain embodiments, the article may comprise or consist essentially of such polymers and / or other materials. Other examples of potentially suitable polymers and other materials are described in detail below. The article may be planar, and in certain embodiments may not be planar (eg, curved). The article may in some cases be formed from a material that is at least partially mechanically deformable, for example, the article is mechanically visible to the average human without the use of tools. It may be made of a material that can be deformed. However, in other embodiments, the article may be formed from a relatively harder material such that the article is not mechanically deformable.

  There may be one or more openings in one or more channels that are used to drain the fluid contained in the channels to the drying area, or in some cases to two or more drying areas. The opening may be, for example, a simple opening or hole in the side of the channel, the open end of the channel, or an additional structure associated with the opening through which the fluid passes before being discharged into the drying area (e.g. There may be pipes or tubes with various cross-sectional areas that can be used to direct or change the flow of fluid. The opening may act as a nozzle that can drain fluid from the channel to the drying area. In some cases, the openings are constructed such that the fluid passing through the openings forms individual droplets or separate droplets. For example, in certain embodiments, the openings may be constructed and arranged so that the fluid forms a droplet spray or droplet mist. In other embodiments, the droplets can be ejected as a regular or stable flow of droplets, for example, as a stream of droplets arranged in tandem.

  There may be any number of fluid channels (including microfluidic channels) in the article, and the channels may be arranged in any suitable configuration. The channels may all be connected to each other, or there may be more than one network of channels. In addition, as described above, one or more openings used to drain fluid contained in the channel may be present in one or more of the channels. In some cases, there are relatively high numbers and / or relatively long channels in the article. For example, in certain embodiments, the channels in the article together have a total length, in some cases, at least about 100 micrometers, at least about 300 micrometers, at least about 500 micrometers, at least about 1 mm, at least about 3 mm, It may be at least about 5 mm, at least about 10 mm, at least about 30 mm, at least 50 mm, at least about 100 mm, at least about 300 mm, at least about 500 mm, at least about 1 m, at least about 2 m, or at least about 3 m. As another example, the article comprises at least one channel, at least 3 channels, at least 5 channels, at least 10 channels, at least 20 channels, at least 30 channels, at least 40 channels, It may have at least 50 channels, at least 70 channels, at least 100 channels, and the like.

  In certain embodiments, at least some of the channels in the article are microfluidic channels. “Microfluidics” as used herein refers to a device, article or system comprising at least one fluid channel having a cross-sectional dimension of less than about 1 mm. The “cross-sectional dimension” of the channel is measured perpendicular to the direction of the net fluid flow in the channel. That is, for example, some or all of the fluid channels of the article may have a maximum cross-sectional dimension of less than about 2 mm, and in certain cases, less than about 1 mm. In one set of embodiments, all fluid channels in the article are microfluidic channels and / or have a largest cross-sectional dimension of about 2 mm or less or about 1 mm or less. In certain embodiments, the fluid channel may be formed in part by a single element (eg, an etched substrate or molded unit). Of course, larger channels, tubes, chambers, reservoirs, etc. can be used to store and / or deliver fluid to various components or systems in other embodiments of the invention. . In certain sets of embodiments, the maximum cross-sectional dimension of the channels in the article is less than 500 microns, less than 200 microns, less than 100 microns, less than 50 microns, or less than 25 microns.

  “Channel” as used herein means a feature on the surface or interior of an article or substrate that at least partially directs the flow of fluid. The channel may have any cross-sectional shape (circular, elliptical, triangular, irregular shape, square or rectangular, etc.) and may be covered or uncovered. In fully covered embodiments, at least a portion of the channel may have a completely closed cross section, or the entire channel may extend the entire length excluding the inlet and / or outlet or opening. May be completely closed along. The channel also has an aspect ratio (length to average cross-sectional dimension) of at least 2: 1, more typically at least 3: 1, 4: 1, 5: 1, 6: 1, 8: 1, 10 :. It may be 1, 15: 1, 20: 1 or more. Open channels generally have properties that facilitate control of fluid movement, such as structural properties (elongated dents) and / or physical or chemical properties (hydrophobic versus hydrophilic) or force on fluids Other characteristics that can be added (eg, containing force). The fluid in the channel may partially or completely fill the channel. In some cases using open channels, the fluid may be retained in the channels using, for example, surface tension (ie, a concave or convex meniscus).

  The channel may be of any size, for example, the largest dimension perpendicular to the net fluid flow is less than about 5 mm or less than 2 mm, or less than about 1 mm, less than about 500 microns, about 200 microns. Less than about 100 microns, less than about 60 microns, less than about 50 microns, less than about 40 microns, less than about 30 microns, less than about 25 microns, less than about 10 microns, less than about 3 microns, less than about 1 micron, less than about 300 nm , Less than about 100 nm, less than about 30 nm, or less than about 10 nm. In some cases, the dimensions of the channel are selected so that fluid can flow freely through the article or substrate. The channel dimensions may also be selected, for example, such that the fluid in the channel has a specific volumetric or linear flow rate. Of course, the number of channels and the shape of the channels may vary according to any method known to those skilled in the art. In some cases, more than one channel may be used. For example, more than one channel may be used, in which case the channels are located adjacent to or close to each other, such as at positions that intersect each other, and so forth.

  In one set of embodiments, the channels in the article are arranged in a quasi two-dimensional pattern. In a “pseudo two-dimensional pattern”, the channels in an article are fluidly connected if all channels in the article are “hidden” from a surface or protrude perpendicularly from that surface. At least one such that any two channels that appear to be in fact are fluidly connected (ie, there is no “bridge” in the article that separates the fluid in separate channels) Constructed and arranged so that one surface can be defined relative to the article. Such articles are useful in certain cases, for example, to simplify manufacturing, fabrication or preparation.

  In certain embodiments, one or more channels in the article may have an average cross-sectional dimension of less than about 10 cm. In certain cases, the average cross-sectional dimension of the channel is less than about 5 cm, less than about 3 cm, less than about 1 cm, less than about 5 mm, less than about 3 mm, less than about 1 mm, less than 500 micrometers, less than 200 micrometers, less than 100 micrometers. Less than 50 micrometers or less than 25 micrometers. “Average cross-sectional dimension” is measured in a plane perpendicular to the net fluid flow in the channel. If the channel is not circular, the average cross-sectional dimension may be considered as the diameter of a circle having the same area as the cross-sectional area of the channel. Thus, the channel may have any suitable cross-sectional shape (eg, circular, oval, triangular, irregular, square, rectangular, or quadrilateral). In certain embodiments, the channel is sized such that laminar flow of one or more fluids contained within the channel occurs.

  The channel may also have any suitable cross-sectional aspect ratio. “Cross sectional aspect ratio” is the largest possible ratio (large value for small value) of two measured values that are made orthogonal to each other with respect to the sectional shape of the channel. For example, the channel may have a cross-sectional aspect ratio of less than about 2: 1, less than about 1.5: 1, and in some cases about 1: 1 (eg, for a circular or square cross-sectional shape). . In other embodiments, the cross-sectional aspect ratio may be relatively large. For example, the cross-sectional aspect ratio is at least about 2: 1, at least about 3: 1, at least about 4: 1, at least about 5: 1, at least about 6: 1, at least about 7: 1, at least about 8: 1, at least It may be about 10: 1, at least about 12: 1, at least about 15: 1, or at least about 20: 1. A relatively large cross-sectional aspect ratio may be used in some implementations to prevent or minimize contact between the fluid in the channel and one or more walls in the channel, as described herein. Useful according to form.

  As described above, the channels can be arranged in any suitable configuration within the article. For example, different channel arrangements may be used to manipulate fluids, droplets, and / or other species within the channel. For example, channels within the article mix fluids and / or droplets or other species contained in fluids to create droplets (eg, separate droplets, single emulsions, double emulsions, or other multiple emulsions, etc.) To screen or sort a fluid and / or droplets or other species contained in the fluid, to separate or split the fluid and / or droplets, for example, between two fluids, a first fluid May be aligned, such as to cause a reaction, between a species carried by and a second fluid, or between two species carried by two fluids. As a specific example, two or more channels may be aligned to create a “flow-focusing” of different fluids in the channels and create droplets.

  Non-limiting examples of systems for manipulating fluids, droplets, and / or other species are described below. Further examples of suitable operating systems can be found in US Patent Application No. 11 / 246,911, filed October 7, 2005 by Link et al., Titled “Formation and Control of Fluidic Species”, July 27, 2006. Published U.S. Patent Application Publication No. 2006/0163385; U.S. Patent Application No. 11 / 024,228 filed December 28, 2004 by Stone et al., Entitled “Method and Apparatus for Fluid Dispersion”, now 2010 U.S. Patent No. 7,708,949, issued May 4, 2004; U.S. Patent Application No. 11 / 885,306, filed Aug. 29, 2007 by Weitz et al., Entitled "Method and Apparatus" s for Forming Multiple Emulsions ", US Patent Application Publication No. 2009/0131543, published May 21, 2009; US Patent Application No. 11 / 360,845 filed February 23, 2006 by Link et al. , The title “Electronic Control of Fluidic Species”, US Patent Application Publication No. 2007/0003442 published on Jan. 4, 2007, each of which is incorporated herein by reference in its entirety. it can.

  The fluid may be delivered to a channel in the article via one or more fluid sources. Any suitable fluid source may be used, in some cases more than one fluid source is used. For example, pumps, gravity, capillary action, surface tension, electroosmosis, centrifugal force, etc. may be used to deliver fluid from a fluid source to one or more channels of the article. Non-limiting examples of pumps include syringe pumps, peristaltic pumps, pressurized fluid sources, and the like. The article may comprise any number of fluid sources associated with the article (eg, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10). Individual or more fluid sources). The fluid source need not be used to deliver fluid to the same channel, for example, the first fluid source can deliver the first fluid to the first channel, while the second fluid The source may deliver a second fluid, such as to a second channel.

  In some cases, two or more channels are arranged to intersect at one or more junctions. There may be any number of fluid channel confluences in the article (eg, 2, 3, 4, 5, 6, or more confluences). As a specific non-limiting example, in certain embodiments, an article includes a first channel having an opening as a nozzle and a second channel that intersects the first channel. The junction of the first channel and the second channel may be upstream of the nozzle, for example, near the junction before the fluid in the first channel is discharged from the nozzle to the drying area. Or may pass through a confluence. Such a configuration includes, for example, a species contained in the first fluid in the first channel to mix the first fluid in the first channel and the second fluid in the second channel; In order to react a second fluid in the second channel and / or a second species contained in the second fluid to form separate droplets of the first fluid in the second fluid; It can be useful, for example, to form a double emulsion or other multiple emulsion between the first fluid and the second fluid.

  In one set of embodiments, a “flow focusing” configuration within the article (here, for example, the first fluid in the first channel to form separate droplets contained in the second fluid). The first fluid fits within the second fluid delivered using the additional channel (eg, the second channel, and sometimes the third channel or additional channel), or the second There may be one, two, three or more channels lined up (enclosed by the fluid). The first fluid and the second fluid may be miscible or immiscible. Such a channel configuration for producing separate droplets is described, for example, in US patent application Ser. No. 11 / 024,228 filed Dec. 28, 2004, entitled “Method and Apparatus for Fluid Dispersion” by Stone et al. “Currently, it can be found in US Pat. No. 7,708,949, issued May 4, 2010, which is hereby incorporated by reference in its entirety. As a non-limiting example, there may be a first channel having an opening as a nozzle, and a second channel and a third channel that intersect the first channel at a common junction. (In other embodiments of the invention, there may be more or fewer additional channels.) The fluid in the second channel and the third channel may be from a common fluid source or It may originate from two different fluid sources, and the fluid in the second channel and the third channel may be the same or different. One or both of the second channel and the third channel may each merge with the first channel at a substantially right angle, or may merge at another suitable angle. In some cases, the second channel and the third channel may merge with the first channel substantially opposite each other, while in other cases, these fluid channels may be at the same merge point. Not all have to intersect.

  As another example, in one set of embodiments, double emulsions or other multiple emulsions are described in, for example, US patent application Ser. No. 11 / 885,306, filed Aug. 29, 2007, entitled “Method” by Weitz et al. and Apparatus for Forming Multiple Emulsions ", US Patent Application Publication No. 2009/0131543, published May 21, 2009, or US Patent Application No. 12/058, filed March 28, 2008 by Chu et al. , 628, entitled “Emulsions and Techniques for Formation”, currently US Pat. No. 7,776,927, issued August 17, 2010, each incorporated herein by reference in its entirety. It may be formed in the channel using the configuration as described). Another suitable technique for preparing double emulsions is the international patent application PCT / US2010 / 000763 filed March 12, 2010, entitled “Controlled Creation of Multiple Emulsions” filed by Weitz et al. WO 2010/104604 published September 16, 2010; or International Patent Application No. PCT / US2010 / 047458, filed September 1, 2010 by Weitz et al., Entitled “Multiple Emulsions Creating Using Junctions” (respectively Which is incorporated herein by reference in its entirety.

  In certain embodiments, the channels are aligned such that the first fluid in the first channel does not contact the walls of the channel when other fluids are added in the channel. For example, after introducing the second fluid into the channel containing the first fluid, the first fluid may not contact any wall defining the channel, so that when viewed from a cross-section, the second fluid Either completely enclosed by the fluid or contained in the second fluid, for example, there is at least one other fluid between the first fluid and the channel wall. Separating the first fluid from the wall of the channel may be due to the introduction of the second fluid, may be due to the degree of miscibility of the first fluid and the second fluid, or the channel contains the fluid Or the like. In certain embodiments, the first fluid may also include one or more species therein, which may not contact any walls that define the channel.

  The first fluid may be present in the second fluid as a continuous flow or as separate droplets. Even preventing the first fluid from contacting the wall of the channel at least proximate to the opening in the channel (eg, it is used to drain the fluid contained in the channel to the drying region). Good. In certain embodiments, the first fluid is prevented from contacting the walls of the channel substantially over the length of the channel. By preventing the first fluid from contacting the channel walls, the reaction or interaction between the first fluid and the channel walls may be reduced or eliminated. For example, the first fluid may include a species (eg, dissolved or suspended in the fluid) that may bind (or “soil”) to the walls of the channel when the species contacts the wall. Reducing or eliminating the ability of species to bind to the wall by preventing, reducing or minimizing contact between the first fluid and the wall. Such binding may be specific or non-specific.

  In certain cases, the channel may be shaped to help prevent the first fluid from contacting any wall that defines the fluid channel. For example, in some cases, the channel may have a relatively large cross-sectional aspect ratio, such as an ellipse or a rectangle. As described herein, the cross-sectional aspect ratio of the channel is at least about 2: 1, at least about 3: 1, at least about 4: 1, at least about 5: 1, at least about 6: 1, at least about 7 :. 1, at least about 8: 1, at least about 10: 1, at least about 15: 1, at least about 20: 1, and the like. Such a channel may be useful, for example, because a portion of the channel wall is positioned relatively away from the first fluid in the channel.

  In addition, in certain embodiments, as described herein, the channel may expand when a fluid (eg, a pressurized fluid) is introduced, thereby allowing the first fluid to flow through the fluid channel. May help prevent contact with any walls that define the. For example, the channel may expand due to the fluid in the channel, which causes at least a portion of the channel wall to bend away from any fluid contained in the channel. See, for example, FIG. 2 and the following example.

  In some embodiments, the channel may be coated. For example, the coating may make the channel walls (or portions thereof) more hydrophobic or more hydrophilic depending on the application. As a specific non-limiting example, the first fluid may be relatively hydrophilic, the channel walls may be relatively hydrophobic, and / or the coating may make the walls more hydrophobic. As a result, the first fluid is generally repelled (not wetted) by the walls of the channel, thereby preventing the first fluid from contacting the hydrophobic walls that define the fluid channel. Useful. As another example, the first fluid may be relatively hydrophobic and the channel walls may be relatively hydrophilic. Typically, a “hydrophilic” material or surface is one that is wetted by water (eg, water on such a surface has a contact angle of less than 90 °), while “hydrophobic” The material or surface has a contact angle greater than 90 °. However, hydrophobicity may be determined from a relative point of view in other embodiments. That is, the first material may be more hydrophilic than the second material (eg, having a smaller contact angle), but these materials may both be hydrophilic or both hydrophobic May be sex.

  Any suitable method may be used to coat or treat the channel walls (or portions thereof). For example, the wall may be treated by oxygen plasma treatment or coated with a sol-gel material that can be used to change the hydrophobicity of the wall. A portion of the sol-gel may be exposed to light (eg, ultraviolet light that can be used to induce chemical reactions in the sol-gel that alter the hydrophobicity of the sol-gel). The sol-gel may contain a photoinitiator that generates radicals when exposed to light. Optionally, the photoinitiator is conjugated with silane or other material in the sol-gel. The radicals thus generated may be used to cause a condensation reaction or a polymerization reaction on the sol-gel surface, thereby changing the hydrophobicity of the surface. As another non-limiting example, the wall may be coated with a metal oxide to change its hydrophobicity. Still other examples are disclosed below and in International Patent Application No. PCT / US2009 / 000850, filed February 11, 2009, entitled “Surfaces, Inclusion Microfluidic Channels, With Controlled Wetting Properties” filed by Abate et al. Yes, published on Oct. 1, 2009, WO 2009/120254, U.S. Patent Application No. 12 / 733,086, filed Feb. 5, 2010 by Weitz et al., Entitled “Metal Oxide Coating on Surface”. Disclosed in US Patent Application Publication No. 2010/0239824, each of which is incorporated herein by reference in its entirety, published September 23, 2010. It has been.

  As yet another example, additional liquid may be added to prevent the precipitating agent from contacting the channel walls or to remove the contacting precipitant. For example, in one set of embodiments, a first fluid containing a species (eg, a drug) is exposed to a second species that precipitates the species. Some of the precipitant may contaminate the walls and channels by contacting one or more walls of the channels. However, a third fluid may also be added, for example from another inlet, to remove this contamination from the walls of the fluid channel. In some cases, a third fluid may be used to enclose other fluids, thereby preventing other fluids from contacting the channel walls. In some cases, the third fluid can dissolve the precipitating agent, thereby reducing or eliminating the possibility that the precipitating agent will remain solid and / or settle on the walls of the channel. Such a fluid may be selected.

  One non-limiting example can be seen from FIG. FIG. 9A shows a schematic diagram of an article comprising microfluidic channels according to one embodiment of the present invention. 9B and 9C are photomicrographs taken of the left and right square portions of FIG. 9A. For these figures, the scale bar represents 100 micrometers. In these experiments, a drug solution (eg, saturated danazol in isopropyl alcohol) was added to the central channel 51 using water in the side channels 52, 53. The two phases form a jet that extends to the second junction, where additional isopropyl alcohol is added from the side channels 61, 62. In some cases, for example, air or other suitable gas (not shown in this figure) may be added to disrupt the fluid flow and form droplets. In FIG. 9C, an enlarged view of the resulting fluid flow is shown. In this figure, the darker shaded portion 70 is caused by the precipitation of danazol at the isopropyl alcohol-water flow interface due to diffusion-based mixing. However, due to the isopropyl alcohol covering surrounding the two inner streams, the precipitated danazol does not contact the channel walls.

  In certain embodiments, there may be one, two, three or more channels lined up to deliver gas to the liquid contained within the channel. The gas may be, for example, air, oxygen, nitrogen, carbon dioxide, argon, and / or another gas. In some cases, the gas is also dehumidified. The gas may originate, for example, from one or more suitable gas sources as described herein. In some cases, the first channel includes a liquid (or two or more liquids) and a gas delivered to the first channel using additional channels (eg, a second channel and a third channel). May be included. One or both of the second channel and the third channel may each merge with the first channel at a substantially right angle (or at another angle), and in certain embodiments, the second channel and The third channel may merge with the first channel substantially opposite each other. A gas may be used, for example, to form separate droplets from the liquid and to be discharged, for example, from a nozzle or channel opening to the drying area. In certain embodiments, the article may comprise such an arrangement of two or more channels. An example of this is shown in FIG. 1, where the first channel 20 and the first fluid source 25; the second channel 30 and the third channel 32 pass the second fluid from the second fluid source 35 to the first The fourth channel 40 and the fifth channel 42 introduce gas (or another third fluid) from the third fluid source 45 into the first channel 20 while introducing into the channel 20. Also good.

  As another non-limiting example, a first channel having an opening as a nozzle may intersect a second channel and a third channel at a common confluence (in other embodiments of the invention, more There may be more or fewer additional channels). The common junction may be at or close to the opening in certain cases. In some embodiments, the gas is heated (eg, to speed up drying), while in other embodiments, the gas may be at ambient temperature or in some cases cooled. Any suitable gas (eg, air, oxygen, nitrogen, carbon dioxide, argon, etc., or any combination thereof and / or other gases) may be used. The gas may be selected to be reactive or inert with the liquid or species contained within the liquid, depending on the application.

  The gas may be delivered to the first channel, for example, via the second channel and / or the third channel. The gas may be at atmospheric pressure, and in some cases, the gas may be pressurized. For example, the pressure of the incoming gas is at least about 0.01 bar, at least about 0.03 bar, at least about 0.05 bar, at least about 0.07 bar, at least about 0.1 bar, at least about 0.2 bar, at least about 0. It may be 3 bar, at least about 0.4 bar, at least about 0.5 bar, at least about 0.7 bar, at least about 1 bar, at least about 2 bar, at least about 3 bar, at least about 4 bar, or at least about 5 bar. When the gas is introduced into the liquid, the liquid can be broken into separate droplets, which in some cases results in the formation of a droplet spray or droplet mist.

  In some embodiments, the droplets have an average diameter of less than about 1 cm, less than about 7 mm, less than about 5 mm, less than about 3 mm, less than about 1 mm, less than about 700 micrometers, less than about 500 micrometers, less than about 300 micrometers. Less than about 100 micrometers, less than about 70 micrometers, less than about 50 micrometers, less than about 30 micrometers, less than about 10 micrometers, less than about 7 micrometers, less than about 5 micrometers, less than about 3 micrometers, or It may be less than about 1 micrometer. As mentioned above, smaller droplets may be preferred in certain cases due to the large surface area to volume ratio. Such droplets will increase the drying rate in the spray dryer and have drying uniformity and other characteristics compared to larger droplets.

  Another set of embodiments uses electrospray technology. For example, an electric field or other suitable electrospray technique can be used to break up the fluid and form droplets. Such techniques may be used instead of using air or other gases to form droplets as described above, or in combination with the use of air or other gases. For example, in some cases, a relatively high electric field or voltage may be applied to the liquid. In some embodiments, the liquid is guided to form a tailor cone (which may have a reduced cross-sectional dimension in the downstream direction as it exits the channel, for example), and the tailor cone passes through the top of the liquid. A jet of jet and a highly charged droplet of liquid breaks the tailor cone as a series of droplets. In some cases, the droplets may be dispersed radially by Coulomb repulsion. The tailor cone is, as is known to those skilled in the art, a shape that is at least partly conductive when exposed to an externally applied induced electric field. In forming the tailor cone, an electric field may be applied to the fluid flow exiting the channel outlet to pass the fluid in the general direction of the fluid flow. The fluid may have a surface charge that is sensitive to an electric field, whereby the electric field attracts the fluid in the direction that the fluid flows, so that the cross-sectional dimension of the fluid flow is A substantially conical shape that is smaller in the flowing direction is formed.

  In certain embodiments, the electric field applied to the fluid is at least about 0.01 V / micrometer, in some cases at least about 0.03 V / micrometer, at least about 0.05 V / micrometer, at least about 0.1. 08V / micrometer, at least about 0.1V / micrometer, at least about 0.3V / micrometer, at least about 0.5V / micrometer, at least about 0.7V / micrometer, at least about 1V / micrometer, at least about 1.2 V / micrometer, at least about 1.4 V / micrometer, at least about 1.6 V / micrometer, or at least about 2 V / micrometer. In certain embodiments, even higher electric field strengths, such as at least about 2 V / micrometer, at least about 3 V / micrometer, at least about 5 V / micrometer, at least about 7 V / micrometer, or at least about 10 V / micrometer or higher. May be used.

  According to a particular aspect of the present invention, the first fluid and the second fluid are contacted and sometimes mixed in an article comprising one or more channels or microfluidic channels prior to spray drying. The first fluid and the second fluid may be miscible or immiscible. For example, the fluid may be immiscible in a time frame that forms a fluid stream (eg, forms a droplet) or in a time frame of reaction or interaction in a channel. As used herein, two fluids are “immiscible” with each other when they are insoluble to the level of at least 10% by weight on the other at the temperature and conditions at which the fluids are exposed to each other. And

  The fluid may be hydrophilic or hydrophobic. For example, in one set of embodiments, the first fluid may be hydrophilic, the second fluid may be hydrophobic, or the first fluid may be hydrophobic, The second fluid may be hydrophilic, or both fluids may each be hydrophilic or hydrophobic, and so on. In some embodiments, more than two fluids may be used. Hydrophobic fluids are generally immiscible with pure water, while hydrophilic fluids are generally miscible with pure water (of course, water is miscible with itself and therefore Water is a hydrophilic fluid).

  As used herein, the term “fluid” generally refers to a material that flows and conforms to the outline of the container. Typically, fluids are materials that cannot withstand static shear stress, and when subjected to shear stress, the fluid undergoes continuous permanent deformation. The fluid may have any suitable viscosity that allows flow of at least a portion of the fluid. Non-limiting examples of fluids include liquids and gases, but may include freely flowing solid particles, viscoelastic materials, and the like.

  In some cases, one or more of the fluids in the article can be, for example, a chemical, biochemical or biological entity, cell, particle, bead, gas, molecule, pharmaceutical agent, drug, DNA, RNA , Including species such as proteins, fragrances, reactive factors, biocides, fungicides, preservatives, chemicals. Thus, a species may be any substance that can be included in a fluid and can be distinguished from a fluid that contains a species. For example, the seed may be dissolved or suspended in the fluid. The species may be present in one or more fluids. If the fluid contains droplets, the species may be present in some or all of the droplets. Additional non-limiting examples of species that may be present include, for example, biochemical species such as nucleic acids (eg, siRNA, RNAi and DNA), proteins, peptides or enzymes. Still other examples of species include, but are not limited to, nanoparticles, quantum dots, fragrances, proteins, indicators, dyes, fluorescent species, chemicals, and the like. As yet another example, when a species is ingested by a drug, pharmaceutical agent, or body, or otherwise introduced into the body, the physiology, such as treating a disease, alleviating symptoms, etc. It can be other species that have a physical effect. In certain embodiments, the drug may be a small molecule drug, eg, a drug having a molecular weight of less than about 1000 Da or less than about 2000 Da.

  In some aspects, the first fluid includes a species dissolved in the fluid, and the species is insoluble (or to a lesser extent) soluble in the second fluid. Upon contacting or mixing the first and second fluids, the species can no longer remain dissolved (eg, at the same concentration as before) and therefore begins to precipitate. In some cases, such precipitation may occur in the channel, for example, in the channel used to drain the fluid contained in the channel through an opening in the channel to the drying region. Thus, in certain embodiments, the channel may contain a precipitating species, for example after the first fluid and the second fluid are in contact.

  In some cases, the precipitating species may deposit on one or more walls that define the channel, or “soil” the walls. As described herein, various techniques may be used, for example, the use of channels with relatively large cross-sectional aspect ratios, the use of one or more fluids to enclose fluids that contain precipitated species, Reduce the fouling of the channel walls due to the use of specific coatings on one or more walls, fluid flow control within the channels, etc., or combinations of these and / or other techniques, and / or Or you may make it not get dirty. Other examples of such techniques for preventing the first fluid or species contained in the first fluid from contacting the wall defining the channel containing the first fluid are also described herein.

  In certain embodiments, as described below, the contact time or mixing time of the first fluid and the second fluid is set, for example, to control the amount of time that the species can settle and form a solid. It may be kept relatively short. For example, for a relatively short period of time, particles such as microparticles or nanoparticles can be formed during the spray drying process, and in some cases, the size of such particles as described herein. The form and the like may be controlled. In certain embodiments, the mixing of the first fluid and the second fluid is controlled so that the precipitated species do not contact the channel walls.

An example of such a system is liquid antisolvent precipitation.
a system associated with the “precipitation” (“LASP”). In general, in LASP, a first solution containing a solute dissolved in a solvent is mixed with a “poor solvent” to cause supersaturation and / or precipitation of solute particles. Typically, the solute is not soluble in the antisolvent or has at least a relatively low degree of solubility in the second liquid. For example, the solubility of the solute in the anti-solvent can be at least one, two, three, four, or five orders of magnitude (10 to the power) less than the solubility of the solute in the solvent. Without wishing to be bound by any theory, it is believed that precipitation occurs there through nucleation and / or growth by agglomeration or condensation. In some cases, uniform mixing conditions may be used to ensure rapid and uniform supersaturation. Examples of possible solutes include, but are not limited to, danazol, ibuprofen, itraconazole, ascorbyl palmitate, fenofibrate, griseofulvin, sulfamethoxazole. Non-limiting examples of solvents include, for example, acetone, dimethyl sulfoxide, tetrahydrofuran, ethanol, or isopropyl alcohol. The poor solvent may be, for example, water, an aqueous solution (for example, a solution containing water as a solvent, for example, saline), or the like. As an example, the anti-solvent may be a liquid that is miscible in water.

  Specific non-limiting examples of such systems are isopropyl alcohol and danazol (17α-ethynyltestosterone) in water. Danazol generally has good solubility in isopropyl alcohol, but its solubility in water is relatively low. Thus, in one set of embodiments, danazol dissolves in isopropyl alcohol to form a first fluid and then contacts water as the second fluid in a channel, such as, for example, a microfluidic channel. When the flow in the channel is laminar, substantial mixing of isopropyl alcohol and water does not occur in the channel (other than due to diffusion), so danazol is generally not included in the channel. Remains dissolved in isopropyl alcohol without substantial precipitation. However, when mixing of the first fluid and the second fluid occurs (eg, by introducing gas into the channel and such mixing occurs), danazol can remain dissolved in the mixed fluid. Thus, it precipitates to form a solid. In some cases, this mixing process may be performed relatively quickly, for example, just prior to the fluid being discharged to the drying area through an opening or nozzle. Thus, while danazol precipitates, the fluid is drained to form droplets that dries while in the drying zone. In this manner, solid particles containing danazol can be formed by spray drying. In some cases, as described herein, the control of the formation of such particles can be controlled, for example, producing relatively monodisperse particles and / or particles that are relatively amorphous. . For example, certain embodiments can result in controlled production of particles (eg, amorphous particles) having a relatively narrow size distribution and / or a low average particle size.

  According to certain embodiments of the invention, the time during which the first and second fluids (eg, solvent and anti-solvent in the case of LASP) are exposed is kept relatively short. For example, the first fluid and the second fluid may be kept separate and then contacted within a channel (eg, a microfluidic channel) in the article. In some cases, the fluid may be contacted in the spray dryer just prior to draining from the channel to the drying area. For example, the first fluid and the second fluid may be contacted and optionally mixed in a channel having one or more openings used to drain the fluid to the drying region.

  As described above, in certain embodiments, the time that the fluid physically contacts before draining to the dry zone may be relatively short, for example, physical contact between the two fluids in the channel. The time is less than about 5 minutes, less than about 3 minutes, less than about 1 minute, less than about 30 seconds, less than about 20 seconds, less than about 15 seconds, less than about 10 seconds, less than about 8 seconds, less than about 6 seconds, about 5 seconds Less than 2 seconds, less than about 4 seconds, less than about 3 seconds, less than about 2 seconds, less than about 1 second, less than about 0.5 seconds, less than about 0.3 seconds, less than about 0.2 seconds, or about 0.1 seconds It may be less.

  As a specific, non-limiting example, referring now to the fluid system 10 of FIG. 8, the first fluid in the first channel from the first fluid source 25 is the junction 23 and the second fluid. The second fluid in the second channel 30 (and / or the third channel 32) originating from the source 35 may be contacted and the two fluids are delivered to the nozzle 12 and discharged to the drying area 15 Is done. In some cases, for example, depending on the flow rate of the fluid in the channel of the first channel 20, the second channel 30 and / or the third channel 32, the contact time of the two fluids can be, for example, As described above, it may be relatively short.

  In some embodiments, the physical contact time of an object within an article can be determined, for example, by using a chamber (eg, for mixing) and / or channel geometry (eg, different dimensions, sizes, lengths, disconnections). It can be controlled using various elements within the article, such as area, shape, etc.). As a specific, non-limiting example, one set of embodiments may use one or more “meandering” channels to control the amount of physical contact time. The serpentine channel may have any suitable size and / or shape, but because of the inherently long channel and its length increase, the physical contact time of the fluid Increase. For example, a serpentine fluid channel may have a zigzag profile or may have another suitable geometry. The appropriate serpentine channel length will vary depending on various factors such as the fluid in contact, the length desired to be exposed, and the flow rate of the fluid in the channel.

  In one set of embodiments, a bolus flow is used to control the mixing of fluid in the channel (eg, mixing of the first fluid and the second fluid). In bolus flow, relatively large objects (eg, large droplets or particles) may substantially fill the channel (eg, the cross section of the channel may be substantially or completely covered by the droplet). . A series of boluses in the channel may delimit or divide the fluid flow in the channel between the boluses into individual compartments, and the fluid in the individual compartments is recirculated. Or may be mixed in other ways. In certain embodiments, the material forming the bolus may be immiscible or substantially insoluble in one or more fluids between the boluses, but in other embodiments, the bolus. The material may be miscible or soluble.

  The bolus may in some cases substantially fill the channel, in which case at the channel cross-section, at least about 50% of the channel is filled with bolus material (eg, solid, liquid, gas, etc.). In certain cases, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, at least about 99% of the channel, or the entire cross section of the channel is bolus Filled with material. In some embodiments, the bolus may delimit or divide the fluid in the channel, in which case the volume of the delimited portion is no more than about 10 ml, no more than about 3 ml, no more than about 1 ml. About 300 microliters or less, about 100 microliters or less, about 30 microliters or less, about 10 microliters or less, about 3 microliters or less, about 1 microliter or less, about 300 nl or less, about 100 nl or less, about 30 nl or less, about 10 nl or less, about 3 nl or less, or about 1 nl or less.

  In certain embodiments, the boluses may be separated on a substantially repeating basis, for example, at a given location in the channel, the bolus has an average frequency of less than about 100 Hz, less than about 50 Hz, less than about 30 Hz, It may pass less than about 10 Hz, less than about 5 Hz, less than about 3 Hz, less than about 1 Hz, less than about 0.5 Hz, less than about 0.3 Hz, or less than about 0.1 Hz (ie, 0.1 Hz is 10 seconds) (Equivalent to passing one bolus through a given location each time). In some embodiments, the bolus has an average volume of about 10 ml or less, about 3 ml or less, about 1 ml or less, about 300 microliters or less, about 100 microliters or less, about 30 microliters or less, about 10 microliters or less, about It may be 3 microliters or less, about 1 microliter or less, about 300 nl or less, about 100 nl or less, about 30 nl or less, about 10 nl or less, about 3 nl or less, or about 1 nl or less.

In some cases, such mixing (e.g., mixing of fluids in the channels, including within the compartments between boluses) may be further facilitated by controlling the channel geometry. For example, the fluid may pass through one or more channels or other systems that change the velocity and / or direction of movement of the fluid. A change in direction may change the convection pattern in the fluid, thereby causing or facilitating mixing in the fluid between boluses. For example, a channel includes a chamber, one or more bends or zigzags, an inflated region, a deflated region, a valve, etc. and / or any other suitable combination of these channel elements and / or other channel elements. You may go out. For example, another example of channel geometry used to control mixing within droplets and / or other fluids contained in the channel is described in US patent application filed February 23, 2006 by Link et al. No. 11 / 360,845, title "Electronic Control of Fluidic"
Species ", U.S. Patent Application Publication No. 2007/0003442, published Jan. 4, 2007, each of which is incorporated herein by reference in its entirety.

  In certain embodiments, the fluid flows through the channel at a relatively high flow rate or velocity, for example, to achieve a contact time as described herein. The flow through the channel may be laminar or turbulent. In some cases, the flow through the channel has a Reynolds number of the flow of at least about 0.001, at least about 0.003, at least about 0.005, at least about 0.01, at least about 0.03, at least about 0. .05, at least about 0.1, at least about 0.3, or at least about 0.5. In other embodiments, a larger Reynolds number (eg, corresponding to turbulence) may be used, for example, a Reynolds number of at least about 1, at least about 3, at least about 5, at least about 10, at least about 30. , At least about 50, at least about 100, at least about 300, at least about 500, or at least about 1000. However, in yet other embodiments, the flow through the channel has a Reynolds number of less than 1000, less than about 300, less than about 100, less than about 30, less than about 10, less than about 3, or less than about 1 It may happen as follows. In still other embodiments of the invention, the volumetric flow rate of the fluid through the channel is at least about 0.01 ml / h, at least about 0.03 ml / h, at least about 0.05 ml / h, at least about 0.1 ml / h. At least about 0.3 ml / h, at least about 0.5 ml / h, at least about 1 ml / h, at least about 3 ml / h, at least about 5 ml / h, at least about 10 m / l, at least about 30 ml / h, at least about 50 ml / H, or at least about 100 ml / h.

  A relatively fast flow rate may be achieved by increasing or controlling the difference between the pressure of one or more fluid sources in the article containing the channel and the pressure in the drying area of the spray dryer. For example, the pressure in the drying region may be atmospheric pressure (approximately 1 atm) and / or the pressure may be higher or lower. As a specific non-limiting example, the pressure in the drying region is less than atmospheric pressure, less than about 50 mmHg, less than about 100 mmHg, less than about 150 mmHg, less than about 200 mmHg, less than about 250 mmHg, less than about 300 mmHg, less than about 350 mmHg, about The pressure may be less than 400 mmHg, less than about 450 mmHg, less than about 500 mmHg, at least 550 mmHg, at least 600 mmHg, at least 650 mmHg, less than about 700 mmHg, or less than about 750 mmHg. As another example, the pressure of one or more fluid sources in the article is at least about 1 bar, at least about 1.1 bar, at least about 1.2 bar, at least about 1.3 bar, at least about 1.4 bar, at least about 1. It may be 5 bar, at least about 1.7 bar, at least about 2 bar, at least about 2.5 bar, at least about 3 bar, at least about 4 bar, at least about 5 bar, and the like.

  When discharged from the channel to the appropriate drying area, in certain embodiments, the fluid condenses, for example by surface tension or other action, to form individual or separate droplets within the drying area. be able to. One skilled in the art will be able to determine the average diameter of a population of droplets using, for example, laser light scattering or other known techniques. The droplets formed in this way may be spherical or, in certain cases, non-spherical. For non-spherical droplets, the droplet diameter may be considered as the mathematically perfect sphere diameter having the same volume as the non-spherical droplet. The droplets may be stably formed, for example, form a stable or linear flow of droplets, or in other embodiments, may form a larger number of droplets, for example, dry Within the region, for example, a mist or spray of individual droplets may be created.

  In some cases, fluid is ejected from the channel such that relatively small droplets are formed, for example, such that the average diameter of the formed droplets is less than about 1 cm. In certain embodiments, as a non-limiting example, the average diameter of the droplets is further less than about 1 mm, less than about 500 micrometers, less than about 200 micrometers, less than about 100 micrometers, less than about 75 micrometers, about 50 micrometers. Less than about 25 micrometers, less than about 20 micrometers, less than about 15 micrometers, less than about 10 micrometers, less than about 5 micrometers, less than about 3 micrometers, less than about 2 micrometers, about 1 micrometer Less than, less than about 500 nm, less than about 300 nm, less than about 100 nm, or less than about 50 nm. Further, the average diameter of the droplets may be at least about 30 nm, at least about 50 nm, at least about 100 nm, at least about 300 nm, at least about 500 nm, at least about 1 micrometer, at least about 2 micrometers, at least about 3 micrometers, in certain cases. It may be at least about 5 micrometers, at least about 5 micrometers, at least about 10 micrometers, at least about 15 micrometers, or at least about 20 micrometers. The “average diameter” of a population of droplets is the arithmetic average of the droplet diameters.

  In certain embodiments, for example, the droplets of fluid in the dry region after being discharged from the channel may be substantially monodispersed. For example, fluid droplets may comprise at least about 50%, at least about 60%, at least about 70%, about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97% of the droplets, Or at least about 99% has a difference from the average droplet diameter of about 10% or less, about 7% or less, about 5% or less, about 4% or less, about 3% or less, about 2% or less, or about 1% You may have a diameter distribution which has the following diameters.

  In some cases, at least a portion of the fluid in individual droplets may harden or solidify, for example, in a dry region. For example, a portion of the droplet and / or a portion of the portion of the droplet may be cured to form particles. The particles may then be collected thereafter. The particles may e.g. harden the first fluid, hardened, depending on the material (e.g. water and / or other volatile fluid) that evaporates or is removed from the fluid droplets in the dry region. The second fluid and / or the species contained in the curing fluid may be included. When two or more types of materials are present, the materials may be uniformly or non-uniformly distributed among the particles. The particles, in certain embodiments, may be substantially the same shape and / or substantially the same size as the fluid droplet. For example, the particles may be monodispersed, for example as described above, and / or the particles may be spherical, and in certain cases may not be spherical. In some cases, some or all of the particles may be microparticles and / or nanoparticles. Microparticles generally have an average diameter of less than about 1 mm (eg, the average diameter of particles is typically measured in micrometers), while nanoparticles generally have an average diameter. Is less than about 1 micrometer (eg, the average diameter of the particles is typically measured in nanometers). In some cases, the particles are at least about 50%, at least about 60%, at least about 70%, about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97% of the droplets, Or at least about 99% has a difference from the average diameter of the particles of about 10% or less, about 7% or less, about 5% or less, about 4% or less, about 3% or less, about 2% or less, or about 1% or less May have a diameter distribution such as

  In one set of embodiments, the particles include species contained within the fluid that are used to form the particles. For example, the first fluid may include a seed, and optionally mix the first fluid with the second fluid, the mixture of the first fluid and the second fluid is discharged, and within the drying region A fluid droplet may be generated. The first fluid and / or the second fluid may be evaporated or removed in the dry area, thereby forming solid particles from the seed in the dry area. Solid particles may be crystalline in certain embodiments, for example depending on the amount of time the droplets or particles are exposed to the dry region, the rate at which the droplets dry and / or solidify to form particles. It may be amorphous or amorphous. As a specific, non-limiting example, the relatively short time for the seed to settle may be useful for forming amorphous particles. For example, if seed precipitation occurs due to the interaction of the first fluid and the second fluid, the time for which the fluid is in physical contact before being discharged to the dry zone is kept relatively short, Formation can be promoted.

  Any technique known to those skilled in the art, such as, for example, X-ray diffraction (XRD) techniques can be used to determine the crystallinity of the particles. In some applications, amorphous particles may be desirable because amorphous particles typically dissolve faster than similar crystalline particles. For example, when using particles as a drug, amorphous particles may exhibit significantly increased bioavailability, for example, compared to similar crystalline particles. In certain embodiments, the particles may exhibit a degree of crystallinity between fully crystalline and fully amorphous. For example, the particles are less than about 90%, less than about 80%, less than about 70%, less than about 60%, less than about 50%, less than about 40%, less than about 30%, less than about 20%, or less than about 10% Average crystallinity (the mass of particles that are crystalline with respect to the total mass of the particles). In certain instances, the particles are at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least May exhibit an average crystallinity of about 90%.

  In certain embodiments, the droplets may further include, for example, a crystallization inhibitor present in the first fluid and / or the second fluid, and / or separately introduced crystallization. Inhibitors may be included. For example, a crystallization inhibitor can reduce crystallization and / or eliminate crystallization in a fluid droplet as the fluid droplet dries, thereby rendering the particle amorphous or Or at least a lower crystallinity and a higher degree of amorphous character. Any suitable crystallization inhibitor can be used depending on the species and / or the fluid to solidify. As a specific non-limiting example, a crystallization inhibitor does not readily crystallize (at least under conditions that form particles) and, in certain embodiments, reduces crystal growth in a pharmaceutical formulation. Or a polymer that can be inhibited (eg, poly (vinyl pyrrolidone)), including, for example, danazol, ibuprofen, or other suitable species as described herein.

  Certain aspects of the present invention are generally directed to techniques for scaling up or “increasing the number” of devices as described herein. For example, in one set of embodiments, a channel may have two or more openings or nozzles that are used to direct multiple drops to a drying area or to two or more drying areas. And may be discharged. As another example, an article may comprise more than one channel, which may be used to discharge a plurality of droplets to a drying area or to more than one drying area. For example, the article comprises at least 2 channels, at least 3 channels, at least 5 channels, at least 10 channels, at least 25 channels, at least 50 channels, at least 100 channels. Alternatively, some or all of the channels may have one or more openings or nozzles. As yet another example, two or more articles may be present, some or all of the articles may have at least one opening, through which the droplets For example, it is discharged to a dry area or to two or more dry areas. As another example, any combination of these may be present.

  When more than one article is present, the articles can independently be substantially the same or different. In certain embodiments, more production of droplets or particles can be achieved, for example, simply by adding a substantially identical replica of the article used to produce the droplets. For example, the spray dryer has at least 2 articles, at least 3 articles, at least 5 articles, at least 10 articles, at least 25 articles, at least 50 articles, at least 100 articles, at least 250 articles, at least 500 articles, at least 1000 articles, etc. may be used, and using these, multiple droplets may be discharged into the drying area or into two or more drying areas May be. The article may draw fluid from a common fluid source or two or more common fluid sources in certain embodiments. In certain embodiments, for example, each article may have its own fluid source.

  Those skilled in the art will be aware of other techniques useful for scaling up or increasing the number of devices or articles as described herein. For example, in some embodiments, a fluid distributor can be used to distribute fluid from one or more inputs to multiple outputs (eg, in one or more devices). For example, a plurality of articles may be connected in three dimensions. In some cases, the channel dimensions are selected so that pressure fluctuations in parallel devices can be substantially reduced. Other examples of suitable techniques include, but are not limited to, international patent application PCT / US2010 / 000753 filed March 12, 2010, entitled “Scale-up of Microfluidic Devices”, 2010/11 by Romansky et al. And those disclosed in WO 2010/104597, which was published on May 16, which is hereby incorporated by reference in its entirety.

  Further aspects of the present invention generally relate to systems and methods for manipulating droplets in channels contained within an article, for example, prior to ejecting the droplets to a drying area. Non-limiting examples of droplet operations include creating droplets, separating droplets, fusing droplets, mixing within droplets, screening droplets, sorting droplets Some of which are described herein. Further non-limiting examples of techniques for manipulating droplets may be found in various documents incorporated herein by reference.

  For example, in certain embodiments, one or more droplets may be created in a channel by generating a charge in a fluid surrounded by a liquid, and the fluid may be separated into individual droplets within the liquid. In some embodiments, an electric field may be applied to the fluid to form droplets. The fluid may exist as a series of individual charged droplets and / or electrically inducible droplets within the liquid. Fluid in a liquid using any suitable technique, for example, by placing the fluid in an electric field (which may be AC, DC, etc.) and / or by reacting and imparting a charge to the fluid A charge may be generated.

  The electric field is, in one embodiment, made from an electric field generator (ie, a device or system capable of generating an electric field that can be applied to a fluid). An electric field generator is an AC field (ie, an electric field that varies periodically with respect to time (eg, sinusoidal, sawtooth, square, etc.)), a DC field (ie, an electric field that is constant over time). A pulse field or the like may be generated. Techniques for generating an appropriate electric field (which may be AC, DC, etc.) are known to those skilled in the art. For example, in one embodiment, an electric field is created by applying a voltage across a pair of electrodes that may be in proximity to the channel such that at least a portion of the electric field interacts with the channel. The electrodes may be made from any suitable electrode material or materials known to those skilled in the art, including but not limited to silver, gold, copper, carbon, platinum, copper, tungsten, tin, cadmium, Nickel, indium tin oxide (“ITO”), and the like, and combinations thereof.

  In another set of embodiments, fluid droplets are removed from the fluid surrounded by the liquid in the channel by changing the dimensions of the channel in a manner that allows the fluid to be directed to form individual droplets. Can be made. The channel may be, for example, a channel that widens in the direction of flow, such that the fluid does not adhere to the channel walls and produces individual droplets, or, for example, the fluid into individual droplets. It may be a channel that narrows with respect to the direction of flow so that it is forced to coalesce with. In some cases, the channels may change dimensions (eg, mechanically or electromechanically, by air pressure) in such a manner as to form individual droplets over time. For example, the channels may be mechanically contracted (“throttle”) to form droplets, or the fluid flow may be mechanically hindered, for example, by the use of moving baffles, rotating blades, etc. May be formed.

  Certain embodiments are generally directed to systems and methods that separate a droplet into two or more droplets. For example, droplets can be separated using an applied electric field. The droplet may have a greater conductivity than the surrounding liquid, and in some cases the droplet may be neutral in charge. In certain embodiments, in an applied electric field, charge may be transferred from the inside of the droplet to the surface and distributed to the surface, thereby canceling the electric field inside the droplet. . In some embodiments, the charge on the droplet surface is also subjected to a force by the applied electric field, thereby moving the charge of opposite polarity in the opposite direction. Due to the transfer of charge, in some cases, the droplet may be pulled apart into two separate droplets.

  Certain embodiments of the present invention typically have two or more droplets typically fused or coalesced, eg, depending on composition, surface tension, droplet size, presence or absence of surfactants, etc. Relates to a system and method for fusing or merging two or more droplets into a single droplet when In certain cases, as compared to the size of the droplet, the surface tension of the droplet can also prevent droplet coalescence or coalescence.

  As a non-limiting example, two droplets are given opposite charges (ie, positive and negative charges, not necessarily the same size), which causes the droplets to fuse or coalesce due to opposite charges. As can occur, the electrical interaction of the two droplets can be increased. For example, an electric field may be applied to the droplet, the droplet may pass through a capacitor, or the droplet may be charged by a chemical reaction. In some cases, the droplets may not coalesce even when a surfactant is applied to reduce the surface tension of the droplets. However, if the droplet is charged with the opposite charge (although not required, it may be the same size), the droplet could be fused or coalesced. As another example, a droplet may not necessarily be charged with the opposite charge (in some cases it may not be charged at all) and may be induced into the droplet to cause the droplets to coalesce. Fusing by using dipoles. Also, it is not always necessary to make the contact “from the front” in order to combine two or more droplets. Any contact angle is sufficient if the fusion of at least some of the droplets begins first. For example, US patent application Ser. No. 11 / 698,298, filed Jan. 24, 2007 by Ahn et al., Entitled “Fluidic Droplet Coalesence”, U.S. Patent Application Publication No. 2007/2007 published on Aug. 23, 2007. See also 0195127 (incorporated herein in its entirety).

  Certain embodiments of the present invention further relate to systems and methods for mixing two or more fluids within a droplet. For example, in various embodiments, two or more droplets may be fused or coalesced, and two or more fluids from two or more original droplets may be mixed. It should be noted that when two droplets fuse or coalesce, complete mixing within the droplet does not occur immediately. Mixing may be done by naturally occurring means such as, for example, by diffusion (eg, through an interface between regions), by reaction between fluids, by the flow of fluid within a droplet (ie, convection). In some cases, mixing can be facilitated by a specific system outside the droplet. For example, a droplet may pass through one or more channels, channel elements, bends, zigzags, valves, etc., thereby changing the velocity and / or direction of movement of the droplet. A change in direction may change the convection pattern within the droplet, causing the fluid to mix at least partially.

  In one set of embodiments, fluid may be injected into the droplet, thereby mixing the injected fluid with other fluids within the droplet. The fluid may in some cases be microinjected into a droplet using, for example, a microneedle or other such device. In other cases, the fluid channel may be used to inject fluid directly into the droplet as it contacts the fluid channel. Other techniques for fluid injection are described, for example, in international patent application PCT / US2009 / 006649 filed December 18, 2009 by Weitz et al., Titled “Particle-Assisted Nucleic Acid Sequencing”, July 15, 2010. Published in WO 2010/080134 (incorporated herein by reference in its entirety).

  Still other embodiments of the present invention are generally directed to systems and methods for screening or sorting droplets, in some cases at a relatively fast rate. For example, the characteristics of the droplets may be sensed and / or determined in a manner (eg, as further described below) and then discharged, for example, into a dry area, or further processing or Droplets may be directed to specific areas of the device so that they are excluded from operation or sent to waste. For example, the properties of the droplet may be sensed and / or determined in some manner, eg, as described herein (eg, the fluorescence of the droplet may be determined) and in response. The electric field may be applied or removed from the droplet and the droplet directed to a specific area (eg, a channel for discharging into a dry area). In some cases, high sorting speeds can be achieved using certain systems and methods of the present invention.

  In one set of embodiments, a charge is created on the drop (eg, as described above) and the applied electric field (which can be an AC field, a DC field, etc.) is used to direct the drop. By doing so, the droplets may be directed. As an example, if necessary, an electric field may be selectively applied or removed (or a different electric field, such as, for example, to direct the droplet to a specific area (eg, within an article). A reverse electric field may be applied). In certain embodiments, the electric field may be selectively applied and removed, if necessary, without substantially changing the liquid flow in the channel containing the droplets. For example, the liquid may flow through the channel on a substantially steady state basis, or on some other predetermined basis, and the droplets contained within the liquid substantially cause the flow of liquid in the fluid system. Without change, for example, an electric field may be used and directed to various regions.

  In another set of embodiments, a dipole is induced in the droplet (initially it may be charged or not charged) and the applied electric field is used to sort or direct the droplet. Depending on the situation, the droplets may be sorted or guided. The electric field may be an AC field, a DC field, or the like. However, in other embodiments, the droplets may be screened or sorted within the fluid system of the present invention by changing the flow of the liquid containing the droplets. For example, in one set of embodiments, droplets are directed or sorted by directing the liquid surrounding the droplet to a first channel, a second channel, and the like.

  In yet another set of embodiments, the pressure in the fluid system, eg, the pressure in different channels, or the pressure in different parts of one channel can be controlled to direct the flow of droplets. . For example, the droplet can be directed to the confluence of the channel, including multiple options for further directions of flow (e.g., at a branch or branch in a channel defining any downstream flow channel). ) The pressure within one or more of any downstream flow channels can be controlled to selectively direct the droplet to one of the plurality of channels, and each successive droplet can be controlled. It is possible to produce a change in pressure approximately according to the time required for the droplets to reach the confluence continuously so that the flow path downstream of the can be independently controlled. In some arrangements, the expansion and / or contraction of the liquid reservoir may be used to direct or sort the droplets into the channel, for example, by directing the movement of the liquid containing the droplets. Non-limiting examples of devices that can expand and / or contract a liquid reservoir include pistons and piezoelectric elements.

  In certain embodiments of the invention, one or more properties of the droplet and / or a portion of the channel containing the droplet (e.g., liquid) so that one or more properties of the droplet can be determined. A sensor is provided that can sense and / or determine the properties of the liquid surrounding the drop, the article containing the channel, etc. Properties that can be determined for a droplet and that can be used in the present invention can be identified by those skilled in the art. Non-limiting examples of such properties include fluorescence, spectroscopy (eg, visible light, infrared, ultraviolet light, etc.), radioactivity, mass, volume, density, temperature, viscosity, pH, material (eg, biological material) Concentration (for example, protein, nucleic acid, etc.). In some cases, a sensor may be connected to a processor, where the processor may perform, for example, work or manipulation on a droplet as described herein.

  As another example, a sensor can sense fluidly, optically or visually, thermally, pneumatically, electrically, etc. to a droplet and / or a portion of a channel that contains the droplet. It may be in a communication state. The sensor may be positioned in the article, eg, close to or away from the channel, but in physical, electrical and / or optical communication with the channel. For example, the sensor may not have any physical connection to the channel containing the droplet, but is positioned to detect electromagnetic waves (eg, infrared, ultraviolet, or visible light) originating from the droplet or channel. May be. The electromagnetic waves may be created by droplets and / or arise from other parts of the channel (or outside the channel or article), for example absorption, reflection, diffraction, refraction, fluorescence, phosphorescence, change in polarity, It may interact with a fluid droplet and / or a portion of a channel containing a fluid droplet in a manner that exhibits one or more characteristics of the fluid droplet through phase changes, changes over time, and the like. Non-limiting examples of sensors useful in the present invention include optical or electromagnetic systems. For example, the sensor may be a fluorescent sensor (eg, stimulated by a laser), a microscope system (which may include a camera or other recording device), and the like. As another example, the sensor may be an electrical sensor, for example, a sensor capable of determining an electric field or other electrical characteristic. For example, the sensor may detect the capacitance, inductance, etc. of the fluid droplet and / or the portion of the channel that contains the fluid droplet.

  Other aspects of the invention include the following. Certain embodiments of the present invention present, for example, a multifunctional tool for developing new formulations. In some cases, for example, small amounts of drugs, pharmaceutical agents or other species can be tested. In certain embodiments, for example, for spray drying properties, a drug, pharmaceutical agent, or other species is tested relatively quickly and / or without requiring a large initial amount of sample for testing. May be. The conditions for spray drying are, for example, spray drying experiments without the need for relatively large amounts of drugs, pharmaceutical agents or other species, in some cases to experiment or optimize various formulations. It may be changed relatively quickly before and / or during the experiment. In certain embodiments, for example, to produce particles, for example, about 100 g or less, about 50 g or less, about 30 g or less, about 10 g or less, about 5 g or less, about 3 g or less, about 1 g or less, about 500 mg or less, about 300 mg or less, or about 100 mg or less of drugs, pharmaceutical agents or other species may be used in the spray dryer. In some cases, in a given spray drying experiment, for example, as described above, conditions may be rapidly changed, for example, to produce relatively few or less mass particles. For example, using a spray dryer, particles of about 100 g or less, about 50 g or less, about 30 g or less, about 10 g or less, about 5 g or less, about 3 g or less, about 1 g or less, about 500 mg or less, about 300 mg or less, or about 100 mg or less A solid may be formed. In certain embodiments, particles having an adjustable composition may be prepared, for example, as described herein. In some cases, the composition of the particles may be easily controlled, for example, by controlling the fluid flow entering the spray dryer.

  In addition, in certain embodiments, the spray dryer may have a relatively low dead volume, thus reducing sample waste and / or as described herein, a drug, pharmaceutical agent or Experiments using minimal amounts of other species may be facilitated. The dead volume of a spray dryer includes the volume within the spray dryer, including the volume of fluid that cannot be discharged into the drying area by the spray dryer during normal spray dryer operation.

  In some cases, suspensions may be made using the spray dryers described herein. For example, such suspensions may be used to increase the dissolution rate and bioavailability of hydrophobic drugs. For example, a suspension can be prepared by spraying a fluid onto a carrier liquid. In certain embodiments, the carrier liquid may contain stabilizers or surfactants, for example as well as a solution. However, in other embodiments, neither stabilizers nor surfactants may be present in the carrier liquid. In some cases, the discharged fluid may be sufficiently dried to produce the particles prior to contact with the carrier liquid. In other cases, however, the fluid may enter, for example, a solution that is not completely dry, forming a liquid suspension in the carrier liquid.

  In addition, in certain embodiments, intermediate processing and / or storage that may result in waste or change in physical or chemical properties, such as transporting fluids into a vial from a collection chamber The spray dryer may be directly connected to vials, sample holders, ampoules and the like. For example, one or more relatively small vials (or other collection chambers) may be used to directly collect material produced by a spray dryer. The vial or other collection chamber has a relatively small volume and may be, for example, less than about 100 ml, less than about 50 ml, less than about 30 ml, less than about 20 ml, less than about 15 ml, less than about 10 ml, less than about 5 ml, etc. . In some cases, one collection chamber is used, while in other cases two or more are used, for example, after a certain time and / or after collecting a certain amount, the next collection chamber May be replaced (manually or automatically).

  In accordance with certain aspects of the present invention, various materials and methods may be used to form articles or elements (eg, channels, chambers such as microfluidic channels) as described herein. For example, various articles or elements may be formed from solid materials, and the channels may include film deposition processes such as micromachining, spin coating, and chemical vapor deposition, including wet chemical processing or plasma processing, laser processing, photolithography. It can be formed by a technique or an etching method. See, for example, Scientific American, 248: 44-55, 1983 (Angel et al.).

In one set of embodiments, the various structures or elements of the articles described herein are polymers, eg, elastomeric polymers, eg, polydimethylsiloxane (“PDMS”), polytetrafluoroethylene (“PTFE”, or (Teflon (registered trademark)) or the like. For example, according to one embodiment, the microfluidic channel may be performed by separately manufacturing the fluid system using PDMS or other soft lithography techniques (details of soft lithography techniques suitable for this embodiment). Yoonan
Xia and George M. et al. The title “Soft Lithography” by Whitesides, published in Annual Review of Material Science, 1998, Vol. 28, pages 153-184, and George
M.M. Whitesides, Emanuel Ostuni, Shuichi Takayama, Xingyu Jiang and Donald E. et al. “Soft Lithography in Biology and Biochemistry” by Ingber, published on Annual Review of Biomedical Engineering, 2001, Vol. 3, pages 335-373, each of which is incorporated herein in its entirety).

  Other examples of potentially suitable polymers include, but are not limited to, polyethylene terephthalate (PET), polyacrylate, polymethacrylate, polycarbonate, polystyrene, polyethylene, polypropylene, polyvinyl chloride, cyclic olefin copolymer (COC), polytetrafluoro Examples include ethylene, fluorinated polymer, silicone, such as polydimethylsiloxane, polyvinylidene chloride, bis-benzocyclobutene (“BCB”), polyimide, and a fluorinated derivative of polyimide. Combinations, copolymers or blends involving polymers are also envisioned, including those described above. The device may also be formed from a composite material, such as a composite of a polymer and a semiconductor material.

  In certain embodiments, the various structures or elements of the article are made from polymeric and / or flexible and / or elastomeric materials, and may be conveniently formed from a curable fluid and manufactured by molding. (For example, replica molding, injection molding, cast molding, etc.). The curable fluid is solidified by induction into a solid that can include and / or transport fluid that is intended to be used in or with a network of fluids. Or essentially any fluid that can spontaneously solidify. In one embodiment, the curable fluid comprises a polymer liquid or a liquid polymer precursor (ie, “prepolymer”). Suitable polymer liquids can include, for example, thermoplastic polymers, thermoset polymers, waxes, metals, or mixtures or composites that have been heated to a temperature above their melting point. As another example, a suitable polymer liquid may include a solution of one or more polymers in a suitable solvent that forms a solid polymer material upon removal of the solvent, for example, by evaporation. . Such polymeric materials can be solidified, for example, from the molten state or by evaporation of the solvent and are well known to those skilled in the art. A variety of polymeric materials, many of which are elastomers, are suitable, and for embodiments in which one or both of the mold masters are composed of elastomeric material, can also be used to form a mold or mold master. Is suitable. A non-limiting list of examples of such polymers includes the general classes of polymers: silicone polymers, epoxy polymers, acrylate polymers. Epoxy polymers are usually characterized by the presence of three-membered cyclic ether groups called epoxy groups, 1,2-epoxides or oxiranes. For example, diglycidyl ether of bisphenol A may be used in addition to compounds based on aromatic amines, triazines, and alicyclic skeletons. Another example is the well-known novolak polymer. Non-limiting examples of silicone elastomers suitable for use in the present invention include those formed from precursors containing chlorosilanes, such as methylchlorosilane, ethylchlorosilane, phenylchlorosilane, and the like.

Silicone polymers, such as silicone elastomer polydimethylsiloxane, are used in certain embodiments. Non-limiting examples of PDMS polymers include Dow Chemical Co. under the Sylgard trademark. , Sold by Midland, MI, specifically Sylgard 182, Sylgard 184, and Sylgard
186. To simplify the manufacture of the various structures of the present invention, silicone polymers including PDMS have several beneficial properties. For example, such materials are not expensive, are readily available, and can be solidified from prepolymer liquids by curing with heat. For example, PDMS can typically be cured by exposing the prepolymer liquid to a temperature of, for example, about 65 ° C. to about 75 ° C., for example, for about 1 hour. Silicone polymers (eg, PDMS) may also be elastomers and are therefore useful in forming very small features with relatively large aspect ratios required in certain embodiments of the invention. Let's go. A flexible (eg elastomeric) mold or master would be advantageous in this regard.

  One advantage of forming a microfluidic structure or channel-like structure from a silicone polymer (eg, PDMS) is the oxidation of such polymers, for example, by exposure to an oxygen-containing plasma (eg, air plasma). As a result, the oxidized structure is capable of crosslinking on its surface with other oxidized silicone polymer surfaces or with oxidized surfaces of various other polymeric and non-polymeric materials. Contains groups. Thus, the structure can be manufactured without the need for a separate adhesive or other sealing means, and then oxidized and other reactive with other silicone polymer surfaces or oxidized silicone polymer surfaces. The substrate surface can be essentially irreversibly sealed. In most cases, sealing can be easily completed by bringing another surface into contact with the oxidized silicone surface without the need to apply auxiliary pressure to form the seal. That is, the pre-oxidized silicone surface acts as a contact adhesive for a suitable engagement surface. Specifically, in addition to being irreversibly sealable to itself, oxidized silicone (eg, oxidized PDMS) can be applied to a range of oxidizing materials other than itself (eg, glass, silicon Can be irreversibly sealed, including silicon oxide, quartz, silicon nitride, polyethylene, polystyrene, glassy carbon, and epoxy polymers), and these oxidized materials can be applied to PDMS surfaces in a similar manner. It has been oxidized (eg by exposure to a plasma containing oxygen). Oxidation and encapsulation methods and overall molding techniques useful in the context of the present invention have been described in the art, see, eg, “Rapid Prototyping of Microfluidic Systems and Polydimethylsiloxane”, Anal. Chem. 70: 474-480, 1998 (Duffy et al.), Which is hereby incorporated by reference in its entirety.

  Thus, in certain embodiments, the design and / or manufacture of a spray dryer can be achieved relatively by using, for example, relatively well known soft lithography and other techniques including those described herein. It can be simple. In addition, in certain embodiments, rapid and / or custom design of the spray dryer is possible, for example, in terms of geometry. In one set of embodiments, for example, when using a spray dryer with a material that is radioactive, toxic, toxic, reactive, biohazard, and / or the material profile (eg, toxicity profile, radioactive profile, etc.) is unknown The spray dryer may be manufactured to be disposable.

  Another advantage of forming channels or other structures (or internal fluid contact surfaces) from oxidized silicone polymers is to make these surfaces much more hydrophilic than the surfaces of typical elastomeric polymers. (A hydrophilic inner surface is desirable). Such hydrophilic channel surfaces can be more easily filled and wetted with aqueous solutions than is possible in structures comprised of typical non-oxidized elastomeric polymers or other hydrophobic materials.

  In certain embodiments, one or more walls or portions of the channel may be coated, for example, with a coating material (including a photoactive coating material). In certain cases, coating materials can be used to control and / or change the hydrophobicity of the channel walls. In certain embodiments, a sol gel is provided that can be formed as a coating on a substrate (eg, the walls of a channel, such as a microfluidic channel). In some cases, one or more portions of the sol-gel may be reacted to change the hydrophobicity. For example, a portion of the sol gel can be exposed to light (eg, ultraviolet light) and used to induce a chemical reaction in the sol gel and change the hydrophobicity. The sol-gel may contain a photoinitiator that generates radicals when exposed to light. Optionally, in the sol-gel, the photoinitiator is conjugated with silane or other material. The radicals thus produced may be used to cause a condensation or polymerization reaction on the sol-gel surface, thereby changing the hydrophobicity of the surface. In some cases, various portions may be reacted, for example, by controlling exposure (eg, using a mask) or left unreacted.

  Thus, in one aspect of the invention, the coating on the channel walls may be a sol-gel. As one skilled in the art knows, a sol-gel is a material that can be in a sol state or a gel state. In some cases, the sol-gel material may include a polymer. The sol state may be converted into the gel state by a chemical reaction. In some cases, the reaction may be facilitated, for example, by removing the solvent from the sol by a drying or heating technique. Thus, in some cases, the sol may be pretreated before use, for example, by causing some condensation within the sol, as described below, for example. The sol-gel chemistry is generally similar to polymerization, but involves a series of hydrolysis of silanes to obtain silanols, followed by condensation of these silanols to form silica or siloxane.

  In certain embodiments, the sol-gel coating may be selected to have specific properties (eg, have specific hydrophobicity). The nature of the coating can be determined by controlling the composition of the sol-gel (eg, by using a particular material or polymer within the sol-gel) and / or for example, as described herein Alternatively, it may be controlled by performing a polymerization reaction and modifying the coating by reacting the polymer to a sol-gel coating.

For example, the sol-gel coating may be made more hydrophobic by incorporating a hydrophobic polymer into the sol-gel. For example, the sol-gel can be one or more silanes, such as fluorosilanes (ie, silanes containing at least one fluorine atom), such as heptadecafluorosilane or heptadecafluorooctylsilane, or other silanes such as methyltria. silanes containing silane (MTES) or one or more lipid chains, e.g., octadecyl silane or other _CH 3 _{(CH 2) n} - silane (n is a may be any suitable integer) include May be. For example, n may be greater than 1, 5 or 10, and in some cases less than about 20, 25 or 30. The silane may also optionally include other groups (eg, alkoxide groups such as octadecyltrimethoxysilane). Other examples of suitable silanes include alkoxy silanes such as ethoxy silane or methoxy silane, halo silanes such as chloro silane, or other silicon containing hydrolyzable moieties (eg hydroxide moieties) Compounds. In general, most silanes may be used in the sol-gel, and a particular silane is selected based on desirable properties such as hydrophobicity. In addition, other silanes (eg, having a short or long chain length) are also selected in other embodiments of the invention depending on the desired factors such as relative hydrophobicity or hydrophilicity. Also good. In some cases, the silane may contain other groups that will render the sol-gel hydrophilic (eg, groups such as amines). Non-limiting examples include diamine silane, triamine silane, or N- [3- (trimethoxysilyl) propyl] ethylenediamine silane. Silanes may react to form a network structure in the sol-gel, and the degree of condensation is controlled by controlling the reaction conditions, for example, by controlling the temperature, the amount of acid or base present, etc. Also good.

In some cases, two or more silanes may be present in the sol-gel. For example, the sol gel may contain fluorosilanes for the resulting sol gel to exhibit higher hydrophobicity and other silanes (or other compounds) that facilitate the production of the polymer. In some cases, to produce a SiO ₂ compound, it is possible to promote condensation or polymerization, there may be a material such as TEOS (tetraethylorthosilicate). In certain embodiments, the silane may have up to four chemical moieties attached to the silane, in which case one of the moieties may be in the RO- moiety and R is, for example, Alkoxides or other chemical moieties so that silanes can be incorporated into metal oxide based networks. In addition, in some cases, one or more silanes can be hydrolyzed to form the corresponding silanols.

In addition, it should be understood that the sol-gel is not limited to only containing silane, and other materials may be present in addition to or in place of silane. For example, the coating may include one or more metal oxides, e.g., SiO _2, vanadia _{(V 2 O} 5), titania _(TiO 2), and / or alumina _(Al 2 _{O 3)} may be contained. As another example, the sol-gel may have a moiety that contains a double bond, otherwise it is reactive in any polymerization reaction, such as, for example, a thiol involved in radical polymerization. .

  The sol gel may be present as a coating on the substrate, and the coating may have any suitable thickness. For example, the coating may have a thickness of about 100 micrometers or less, about 30 micrometers or less, about 10 micrometers or less, about 3 micrometers or less, or about 1 micrometers or less. In some cases, for example, in applications where higher chemical resistance is desired, a thicker coating may be desirable. However, for other applications, such as in relatively small microfluidic channels, thinner coatings may be desirable.

  In one set of embodiments, the hydrophobicity of the sol-gel coating can be controlled, for example, so that the first portion of the sol-gel coating is relatively hydrophobic and the second portion of the sol-gel coating is the first The hydrophobicity can be relatively larger or smaller than the portion. Techniques known to those skilled in the art can be used to determine the hydrophobicity of the coating using, for example, contact angle measurements as disclosed herein. For example, in some cases, a first portion of a substrate (eg, in a microfluidic channel) may have a hydrophobicity that prefers an organic solvent over water, while a second portion is organic It may have a hydrophobic property that favors water over a solvent.

  For example, the hydrophobicity of the sol-gel coating can be modified by subjecting at least a portion of the sol-gel coating to a condensation or polymerization reaction and reacting the polymer with the sol-gel coating. The polymer that reacts with the sol-gel coating may be any suitable polymer and may be selected to have certain hydrophobic properties. For example, the polymer may be selected to be more hydrophobic or more hydrophilic than the substrate and / or sol-gel coating. As an example, a hydrophilic polymer that can be used is poly (acrylic acid).

  The polymer may be added to the sol-gel coating by feeding the polymer in monomeric (or oligomeric) form to the sol-gel coating (eg, in solution) and performing a condensation or polymerization reaction between the polymer and the sol-gel. For example, free radical polymerization may be used to bind the polymer to the sol-gel coating. In certain embodiments, the reactants are optionally subjected to heat and / or light (e.g., ultraviolet (UV) (UV) in the presence of a photoinitiator that can generate free radicals upon exposure to light (e.g., via molecular cleavage). ) Exposure to light) may initiate the reaction (eg, free radical polymerization). Those skilled in the art will recognize many such photoinitiators. Many of the photoinitiators are commercially available, for example, Irgacur 2959 (Ciba Specialty Chemicals), aminobenzophenone, benzophenone, or 2-hydroxy-4- (3-triethoxysilylpropoxy) -diphenyl ketone (SIH6200.0, ABCR GmbH & Co. KG).

  A photoinitiator may be included with the polymer added to the sol-gel coating, or in some cases a photoinitiator may be present in the sol-gel coating. Further, in some embodiments, a photoinitiator may be introduced into the sol-gel coating after the coating process. As an example, a photoinitiator may be included in the sol-gel coating and may be activated upon exposure to light. Further, a photoinitiator may be conjugated or bound to a component of the sol-gel coating (eg, silane). As an example, a photoinitiator (eg, Irgacur 2959) may be conjugated to a silane-isocyanate via a urethane bond (the primary alcohol on the photoinitiator is responsible for nucleophilic addition with isocyanate groups. Which can produce urethane bonds).

  Accordingly, certain aspects of the present invention are generally directed to systems and methods for coating at least a portion of a substrate with such a sol gel. In one set of embodiments, a substrate (eg, a microfluidic channel) is exposed to a sol and then processed to form a sol-gel coating. In some cases, the sol may be pretreated to cause partial condensation or polymerization. Excess sol-gel coating may optionally be removed from the substrate. In some cases, for example, as described above, a portion of the coating is treated with its hydrophobicity by subjecting the coating to a solution containing the monomer and / or oligomer and condensing or polymerizing the monomer and / or oligomer with the coating. Sex (or other properties) may be altered.

  The sol may be contained in a solvent and may also contain other compounds such as photoinitiators including those described above. In some cases, the sol also includes one or more silane compounds. For example, the sol may be processed to form a gel using any suitable technique by removing the solvent using chemical or physical techniques (eg, heat). For example, the sol may be exposed to a temperature of at least about 50 ° C., at least about 100 ° C., at least about 150 ° C., at least about 200 ° C., or at least about 250 ° C., which can be used to remove at least a portion of the solvent, Or you may evaporate. As a specific example, the sol may be exposed to a hot plate set to reach a temperature of at least about 200 ° C. or at least about 250 ° C., and exposing the sol to the hot plate removes at least a portion of the solvent. Or evaporate. However, in some cases, the sol-gel reaction may proceed even in the absence of heat, for example, at room temperature. Thus, for example, the sol may be left for a while (eg, about 1 hour, about 1 day, etc.) and / or air or other gas or liquid can be passed over the sol to advance the sol-gel reaction. Let's go.

In other embodiments, other initiating techniques may be used instead of or in addition to the photoinitiator. Examples include, but are not limited to, redox initiation and pyrolysis caused, for example, by heating a portion of the device (eg, having a certain temperature or oxidizing or reducing chemical) Can be carried out by a liquid flow comprising). In another embodiment, surface functionalization may be achieved by polyaddition and polycondensation reactions, for example, when the surface contains reactive groups that may participate in the reaction. In some cases, silanes containing the desired functional groups may be added, such as silanes containing COOH moieties, NH ₂ moieties, SO ₃ H moieties, SO ₄ H moieties, OH moieties, PEG chains, and the like.

  In some cases, any non-gelled sol still present may be removed from the substrate. Ungelled sols may be actively (eg, physically) removed, for example, by applying pressure or by adding a compound to a substrate, or in some cases, gelled. Sol may be passively removed. For example, in certain embodiments, the sol present in the microfluidic channel is heated to evaporate the solvent and accumulate in a gaseous state in the microfluidic channel, thereby increasing the pressure in the microfluidic channel. This pressure may in some cases be sufficient to remove at least a portion of the ungelled sol or “blow off” the microfluidic channel.

  In certain embodiments, a portion of the coating may be treated and its hydrophobicity (or other property) changed after the coating is introduced to the substrate. In some cases, as described above, the coating is exposed to a solution containing monomers and / or oligomers and then condensed or polymerized to bind to the coating. For example, a portion of the coating may be exposed to heat or light (eg, ultraviolet light), which may be used to initiate a free radical polymerization reaction and polymerization to occur. In some cases, for example, a photoinitiator is present in the sol-gel coating to facilitate this reaction. In certain embodiments, the photoinitiator may also include other reactive groups such that double bonds, thiols, and / or monomers and / or oligomers can be covalently bonded to the sol-gel coating.

The following documents are hereby incorporated by reference in their entirety: US Patent Application No. 11 / 246,911, filed October 7, 2005 by Link et al., Entitled “Formation and Control of Fluidic Species”, US Patent Application Publication No. 2006 published on July 27, 2006. US patent application Ser. No. 11 / 024,228, filed Dec. 28, 2004 by Stone et al., Titled “Method and Apparatus for Fluid Distribution”, now published on May 4, 2010 U.S. Patent No. 7,708,949; U.S. Patent Application No. 11 / 885,306 filed August 29, 2007 by Weitz et al., Entitled "Method and Apparatus for Forming Multiple". Emulsions ", U.S. Patent Application Publication No. 2009/0131543, published May 21, 2009; U.S. Patent Application No. 11 / 360,845, filed February 23, 2006 by Link et al., Titled" Electronic ".
Control of Fluidic Species ", U.S. Patent Application Publication No. 2007/0003442, published January 4, 2007. Also, US Provisional Patent Application No. 61 / 425,415, filed Dec. 21, 2010 by Abate et al., Entitled “Spray Drying Techniques”, US Provisional Application filed May 11, 2011 by Abate et al. Patent application 61 / 485,026, the title “Spray Drying Techniques” is also incorporated herein by reference in its entirety.

  The following examples are intended to illustrate particular embodiments of the present invention and are not intended to exemplify the full scope of the invention.

Example 1
Spray drying is an important technique that can dry a solution, emulsion or suspension in one step. The final product may be a fine powder with a large surface. The pharmaceutical applications of spray drying technology include a wide range of fields, from the production of dry plant extracts that avoid the degradation of heat sensitive ingredients to the production of excipients for compression with improved binding properties. However, conventional spray dryer technology often results in high manufacturing costs because the manufacturing process involves high pressure or complex experimental settings. In addition, particle sizes less than 100 nm, often required for targeted drug delivery, are usually not achieved with commercial spray dryers.

  As described in this example, these limitations can be overcome using microfluidics. One prior art technique for producing fairly sophisticated microfluidic devices is soft lithography using polydimethylsiloxane ("PDMS"). However, hydrophobic compounds can adsorb on PDMS microchannels and foul devices. An improved system for producing nanoparticles from hydrophobic drugs combines the ability to process hydrophobic drugs by spray drying with the versatility of microfluidics.

  Thus, this example is generally directed to the production of hydrophobic drug nanoparticles using a microfluidic spray dryer. The device geometry using this particular embodiment has a high aspect ratio and becomes hydrophilic upon oxygen plasma treatment. This prevents the adsorption of hydrophobic precipitates to the walls of the channel, and hydrophobic drugs can be used in this PDMS microfluidic device. By controlling the distance at which the spray is collected, the crystallinity of the product may be controlled. Therefore, this microfluidic device can produce drug nanoparticles having a diameter of less than 100 nm, for example. In addition, the device can form an amorphous coprecipitate in some cases, for example by spray drying the drug together with a crystallization inhibitor to increase the bioavailability of the hydrophobic drug. . In addition, drug coprecipitates can be prepared using two independent solvent flow injections as described herein.

  In conventional spray dryers, a single liquid stream is typically atomized by the compressed gas of the spray nozzle, and this spray is then mixed with the heated gas stream in the drying chamber to evaporate the solvent. To obtain a dry product. However, this setting can only handle a single solvent system or a premixed solvent mixture. Additional separate injection channels may be provided in the spray dryer to handle the multiple separate solvent streams required to react quickly with the solvent / antisolvent precipitation or solvent stream. In this example, a microfluidic device having an array of two intersecting junctions where the flow is focused is used, as shown in FIG. 1, and in FIG. 1, for forming nanoparticles from a hydrophobic drug by spray drying. The schematic diagram of a microfluidic device is shown.

  This device geometry allows the two solvent streams to be injected separately and provides a third inlet for compressed air. To form the hydrophobic drug nanoparticles, the hydrophobic drug may be dissolved in an organic solvent, which is injected into the first inlet (“Solvent 1”) and the second fluid is injected into the second inlet. ("Solvent 2"). The two solvents may be injected in a manner that forms a jet at the first crossing point, which extends to the second crossing point where compressed air is injected ( "air"). By injection of compressed air, separate droplets, such as sprays or mists, can be formed from the fluid.

  In order to process hydrophobic drugs, the PDMS device should be resistant to soiling due to drug crystals or other precipitating agents adsorbing to the walls of the microchannel. In this example, this was achieved by treating an essentially hydrophobic PDMS device with an oxygen plasma in order to make the spray dryer channel more hydrophilic. The hydrophilicity of the plasma-treated device decreases with time, but the channel surface can be regenerated in the same manner, for example, multiple times. To further improve the resistance to soiling, surface contact between the drug-loaded solvent stream and the channel walls was minimized. This has been achieved by designing device geometries with high aspect ratios. The aspect ratio (height relative to the channel width) was 10: 1 for the upper half of the device and 4: 1 for the spray nozzle. Channels with high aspect ratios are less pressure resistant than square channels, so the channels of the spray dryer may in some cases expand somewhat as shown in FIG.

  In order to determine the effect of channel deformation on the flow profile, a typical solvent / anti-solvent system was processed with the spray dryer of the present invention and the device deformation within the device was compared at low and high pressures. These observations were supported by the results of computational fluid dynamics (CFD) simulations using COMSOL 4.0a. A 3D simulation model was designed that takes into account the structural mechanics of the PDMS channel, the fluid flow shown by the Navier-Stokes equations, and the diffusion of the solvent flow.

For the low pressure spray experiment, the solvent (isopropyl alcohol, IPA), poor solvent (water), compressed air, IPA flow rate 1 ml h ⁻¹ , water water flow rate 10 ml h ⁻¹ respectively, 2 inlets, 3 inlets. As shown in FIG. 2A, the air pressure was set to 0.34 bar. For experiments at high pressure, elevated IPA and water flow rates up to 5 ml ^{h -1} and 50 ml h ^-1 respectively, as shown in Figure 2B, it was set the pressure of the air in 2.09Bar. At low pressure (0.34 bar), the PDMS device showed minimal deformation and a two-dimensional focused flow pattern was seen between the first and second intersections. However, as pressure was increased, the PDMS device responded to internal stress and the channel expanded slightly. Due to the high aspect ratio, the microchannel showed the greatest expansion in the horizontal direction transverse to the fluid flow. The wall of the channel was adapted to be pseudo-circular.

  This deformation affected the flow profile inside the spray dryer, as shown in FIG. 2C. A CFD simulation was used to investigate the effect of deformation on the flow profile. As shown by the simulation of this device, the flow profile between the first and second intersection points took a three-dimensional coaxial flow pattern. As shown in FIG. 2C, the initial rectangular microchannels expanded and became pseudo-circular. As shown by the simulation of this device, the flow profile between the first and second intersection points takes a three-dimensional coaxial flow pattern, and therefore the drug loaded solvent flow and channel flow. The contact surface between the walls becomes smaller. The scale bar indicates 100 micrometers. The inner phase was therefore surrounded by a protective sheath of the central phase. This minimizes surface contact between the solvent in which the hydrophobic drug is dissolved and the walls of the channel and prevents the spray dryer from becoming dirty.

When forming a spray, the shape of the spray and the size of the drops are important factors that affect the dryness, particle size, and morphology of the treated drug. In order to determine the size of the drops and the shape of the spray, the spray formation in the spray dryer was visualized by a recorded video using a high speed camera. IPA was injected into the first and second inlets at a total flow rate of 50-55 ml h- ¹ . At low air pressure, as shown in FIGS. 3A-3C, a jet of fluid is ejected from the nozzle and broken downstream into single droplets, and the solvent stream is not dispersed in the spray, instead. A liquid jet was ejected from the spray nozzle and was broken into large droplets due to Rayleigh plateau instability, as shown in FIGS. The scale bar of all panels shows 100 micrometers. As the air pressure was increased above 0.5 bar, the formation of finely dispersed drops with the spray nozzle was observed, resulting in a round, full cone spray pattern. This pattern was formed because the liquid was turbulent before the orifice in the short outlet channel.

  To quantify the spray formation process, the drop size (diameter) d was measured as a function of air pressure p as shown in FIG. 3D. As the pressure is increased, the average droplet size decreases linearly. This line is a guide for the eyes. The size of the drop decreases linearly as the pressure increases to 2.1 bar with a diameter of about 4 micrometers, and this pressure causes this particular spray dryer to peel off the PDMS coupled by the plasma. It is the maximum pressure that can withstand. However, in other embodiments, higher air pressure may be achieved, for example, by increasing the pressure resistance of the PDMS device by increasing the spacing between the microchannels.

(Example 2)
This example demonstrates the formation of hydrophobic drug nanoparticles using a microfluidic spray dryer according to one embodiment of the present invention. In this example, danazol was used as a model drug. Danazol is an isoxazole derivative of testosterone and is applied in the treatment of endometriosis and hereditary angioedema. The following structure

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  One method for treating hydrophobic drugs is liquid anti-solvent precipitation (“LASP”), in which a drug dissolved in alcohol is precipitated by mixing water as a poor solvent and a drug solution. In this example, danazol was dissolved in isopropyl alcohol and then injected with water at the first intersection. When the microfluidic device was operated with a laminar flow regimen, only mixing based on solvent flow diffusion was observed at the interface and no drug precipitation occurred.

To assess the effect of microfluidic treatment on the particle size and morphology of hydrophobic drugs, neither stabilizers nor surfactants that affect particle growth were added. Flow rate, initially 5 ml ^{h -1,} the water is set to 50 ml h ^-1 for danazol, this flow rate corresponds 1:10 by volume, in the conventional LASP process, the microparticles of danazol is obtained It is shown. The spray in this example was completely suspended in air, thus ensuring that the product was dry when collected. The morphology and particle size of the treated drug was examined by scanning electron microscopy (“SEM”) analysis. Raw (raw) danazol is composed of irregularly shaped particles of about 2 micrometers to 100 micrometers, and in this example, by treating the drug using a microfluidic spray dryer. The particle size was significantly reduced. As shown in FIGS. 4A and 4C, danazol nanoparticles with a narrow particle size distribution (“PSD”) between 20 nm and 60 nm are obtained, which is smaller than that already reported. The scale bar indicates 300 nm.

  The formation of drug nanoparticles using LASP was driven by mixing the drug solution and the antisolvent. The degree of supersaturation of the drug solution appeared to dominate nucleation and drug nanoparticle growth. However, only sufficient mixing occurred in the short outlet channel prior to the spray nozzle orifice of our microfluidic device. Because the high flow rate was used to form a stable spray, the fluid lag time in the outlet channel was too short to allow nuclei to grow by mixing. Therefore, in order to further test this formation process, in certain experiments, the antisolvent (water) was replaced with solvent (IPA), and the danazol IPA solution and pure IPA were converted to the first inlet and the second of the microfluidic device, respectively. Injection into 2 inlets.

  As can be seen from FIGS. 4B and 4D, danazol nanoparticles of the same size and morphology were obtained. The scale bar indicates 300 nm. The formation of danazol nanoparticles of the same size and form in the absence of an anti-solvent suggests that particle formation is driven primarily by spray evaporation and not by nucleation due to supersaturation. It was. From the energy dispersive X ray (“EDX”) analysis of untreated (“raw”) danazol and treated danazol (“spray”) (FIG. 4E), which solvent system was used However, it was also shown that the chemical composition of the drug remained unchanged during the spray drying process.

(Example 3)
Another important parameter of the spray drying process is the final particle collection distance from the nozzle to the drying area. It is known that the form and size of the hydrophobic drug depends on the initial concentration of the reactants, the choice of additives, the ratio of solvent to antisolvent, etc., but the spray space as described herein. It has also been found that by sampling it depends significantly on the collection distance.

  To illustrate this, in this example, danazol was injected with IPA as before, but this time the spray was collected at a 5 cm stage from the spray nozzle. SEM analysis was performed and found that there were two distinct product forms. When the collection distance was 5 cm, aggregates of each layer of danazol were observed, and the thickness of each layer was 60 nm to 80 nm as shown in FIG. 5A. These values closely approximated the size of a single danazol nanoparticle, as shown in FIG.

  However, because the time of flight was too short to allow the spray to evaporate completely, the remaining solvent increased the mobility of the already formed particles, they fused and reached an energetically more favorable state . Therefore, extending the collection distance to 30 cm so that the spray was completely evaporated formed a single nanoparticle as shown in FIG. 5B. FIG. 5B shows that the nanoparticles had a diameter of about 20 nm to 60 nm and gathered in a dense network structure.

  X-ray powder diffraction analysis (“XRPD”) was used to determine the effect of spatial sampling on the crystallinity of danazol. For the XRD pattern of untreated danazol, the characteristic peak at 2θ (2 theta) of 15.8, 17.1, 19.0 was used as a reference. In treated danazol, the intensity of the characteristic peak decreased with increasing spray collection distance. This suggested that the initial crystallinity of the drug did not recover, as shown in FIGS. These figures show that nanoparticles having a diameter of 20 nm to 60 nm gathered in a dense network structure. The generation of amorphous danazol is important because differences in the physicochemical properties of the amorphous form can significantly increase the bioavailability of danazol in some embodiments.

Example 4
Another method for producing amorphous hydrophobic drugs is the simultaneous spray drying of drug and crystallization inhibitor. This example demonstrates this spray drying using a microfluidic spray dryer.

In one experiment, as shown in FIG. 6A, dry danazol in IPA was co-sprayed with water and the spray collected at a short distance. In particular, when danazol in IPA was mixed with water in a microfluidic device and the spray was collected at a distance of 5 cm from the nozzle, danazol grew into crystalline aggregates as shown by the XRPD pattern. This spray did not seem to evaporate completely due to the short flight time. This allowed danazol to grow into star-shaped crystalline aggregates, as shown in FIGS. 6C and 6E. However, in other experiments, amorphous danazol may be formed by using a crystallization inhibitor. Poly (vinyl pyrrolidone) (PVP) is well known to inhibit crystal growth in pharmaceutical formulations and was used in these experiments. As shown in FIG. 6B, Danazol in IPA was treated with 1.5 wt% PVP aqueous solution at the same flow rate of 25 ml h ⁻¹ . Again, the spray was collected at a short distance. However, as the spray dried, danazol precipitated from the spray in the PVP matrix without crystallization, as shown in FIG. 6D. Therefore, as shown in FIG. 6F, no characteristic peak was observed in the XRPD pattern (compare with FIG. 6E). The scale bar in FIGS. 6C and 6D indicates 5 micrometers.

(Example 5)
This example compares an experiment performed using a spray dryer as described herein with an experiment using the same formulation in a conventional laboratory spray dryer. The results are compared using XRPD (X-ray powder diffraction analysis) and SEM.

In these experiments, a Mini spray dryer B 191 (Buechi, Germany) with a spray rate of 10 mg min ⁻¹ was used and tested for danazol IPA solution and danazol IPA solution containing PVP. In the former case, particles in the range of about 1 micrometer to 5 micrometers were made (FIG. 7A), which were significantly larger than the danazol particles formed using the microfluidic spray dryer described above. In addition, the crystallinity of danazol was retained as shown in FIG. 7C. Similar results were observed for the formation of danazol and PVP coprecipitates, as shown in FIGS. 7B and 7D. Although the initial crystallinity of danazol was suppressed by PVP, the particles were 2 orders of magnitude larger than comparable experiments using the microfluidic device described above.

(Example 6)
This example illustrates the various techniques used in the previous examples.

  PDMS microfluidic devices were manufactured using soft lithography. All channels were fixed at a height of 100 micrometers. The PDMS replica was bonded to a flat sheet of PDMS cured using oxygen plasma treatment. The microchannel was temporarily rendered hydrophilic by plasma treatment. The device was flushed with deionized water to maintain a hydrophilic surface modification suitable for handling hydrophobic drugs. Spray dryer nozzles were prepared by slicing the outlet channel of the stamped device with a razor blade. In order to obtain reproducible accuracy when slicing thinly, a guide to the eyes with the initial AutoCAD design was used in the spray dryer.

Spray drying experiment. PVP (weight average molecular weight MW 10,000 g mol ⁻¹ ) and all other chemicals are available from Sigma-Aldrich Co. unless otherwise noted. Obtained from. Danazol (99.9%) was obtained from Selectchemie AG. Water with a specific resistance of 16.8 MΩ cm ⁻¹ (mega ohm / cm) is prepared using a Millipore Milli-Q system. All solutions were filtered through a 0.2 micrometer PTFE filter (Millipore). Each experiment was conducted over 2 hours to demonstrate the long-term stability of the process of forming danazol nanoparticles in a microfluidic spray dryer. An IPA saturated solution of danazol was injected at 5 ml h ⁻¹ at the first inlet and water or IPA was injected at 50 ml h ⁻¹ at the second inlet. To form a coprecipitate, PVP in water (1.5% w / w) was injected into the second inlet at 50 ml h ⁻¹ . To form a spray, air was injected at 2.1 bar into the third inlet. The spray was discharged into air and dried at room temperature, yields ranging from about 70% to about 95%, depending on the experiment and experimental conditions. This spray was imaged at 64,000 fps using a Phantom v9.1 camera (Vision Research). Droplet size was obtained by measuring the size of at least 200 drops with high-speed camera images.

Treated danazol was collected at a distance of 5 cm and 30 cm from the spray nozzle. For SEM analysis, the spray was collected on a glass slide and coated with Pd / Pt. An Ultra55 Field Emission SEM (Zeiss) fitted with an EDX detector was used. The size distribution of the nanoparticles was determined by image analysis of SEM photographs using ImageJ. For XRPD analysis, the sample was collected in an aluminum box fitted with a spray dryer. XPRD analysis was performed using a Scintag XDS2000 powder diffractometer (Scintag, Cupertino, Calif., USA) with Cu Kα (K-alpha) radiation at 40 kV, 30 mA. The XRD pattern was photographed at room temperature using a scanning speed of 1 ° min ⁻¹ and a single step size of 0.02 ° in the range of 10 ^o <2θ <50 ^o (2 theta).

  Although several embodiments of the present invention have been described and illustrated herein, those skilled in the art will implement the function and / or result and / or one or more advantages described herein. Various other means and / or configurations for obtaining will be easily conceived. Each such variation and / or modification is considered to be within the scope of the present invention. More generally, those skilled in the art will appreciate that all parameters, dimensions, materials, and configurations described herein are illustrative and that the actual parameters, dimensions, materials, and / or configurations are It will be readily understood that it will vary based on the specific application in which the teaching is used. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalent examples to the specific embodiments of the invention described herein. Accordingly, the foregoing embodiments have been presented by way of example only and, within the scope of the appended claims and their equivalents, are specifically described in ways other than those specifically set forth and claims. It should be understood that the present invention may be practiced. The present invention is directed to each individual feature, system, article, material, kit, and / or method described herein. In addition, any combination of two or more such features, systems, articles, materials, kits and / or methods is mutually inconsistent with such features, systems, articles, materials, kits and / or methods. If not, it is included in the scope of the present invention.

  Any definitions defined and used herein should be understood to supersede the dictionary definitions, the definitions of documents incorporated by reference, and / or the ordinary meaning of the terms being defined.

  The indefinite articles “a” and “an”, as used in the specification and claims, unless stated to the contrary meaning “at least It should be understood to mean "one".

  The phrase “and / or”, as used in the specification and claims, exists “either or both” of the elements bound by this phrase, ie, in some cases, connected. , And should be understood to mean elements that are present in a disjunctive manner. Multiple elements listed with “and / or” should be construed in the same manner. That is, “one or more” of the elements connected in this way. There may optionally be other elements other than those specifically identified in the “and / or” section, whether or not they are related to the elements specifically identified. Thus, as a non-limiting example, reference to “A and / or B” when used in combination with a non-limiting term such as “comprising”, in certain embodiments, only A (if May include elements other than B), and in another embodiment, may refer only to B (optionally including elements other than A), and in yet another embodiment, A and B May be pointed to (both in some cases including other elements).

  As used herein in the specification and in the claims, “or” should be understood to have the same meaning as “and / or” as defined above. For example, when separating items in a list, “or” or “and / or” should be construed as inclusive, ie include at least one of a number of elements or a list of elements. Should be construed as including more than one and possibly further items not on the list. Terms that clearly have a different meaning, such as “only one of” or “exactly one of” or “consisting of” as used in the claims. "Will refer to including exactly one element of many elements or lists of elements. In general, the term “or”, as used herein, is an exclusive term (eg, “any”, “one of”, “only one of” or “ If exactly one of ")" precedes, it is interpreted as indicating only an exclusive option (ie, "one or the other, not both"). “Consisting essentially of”, when used in the claims, has the usual meaning used in the field of patent law.

  As used herein and in the claims, the phrase “at least one” associated with a list of one or more elements is at least selected from any one or more elements in the list of elements. Means one element, but does not necessarily include at least one of each and every element specifically listed in the list of elements, and any combination of the elements in the list of elements It should be understood that is not excluded. This definition also includes elements other than those specifically identified in the list of elements referred to by the phrase “at least one”, whether or not they have a relationship with the elements specifically identified. Is allowed to exist in some cases. Thus, as a non-limiting example, “at least one of A and B” (or the equivalent expression “at least one of A or B” or the equivalent expression “of A and / or B, "At least one") may in some embodiments include at least one (optionally two or more) A and may indicate that B is absent (optionally including elements other than B); May include at least one (optionally two or more) B and may indicate that A is not present (optionally includes elements other than A), and in yet another embodiment, at least May include one (optionally two or more) A and at least one (optionally two or more) B (may include other elements). .

  In the case of any method involving two or more steps or actions claimed in the claims, unless the context clearly indicates otherwise, the order of the steps or actions of the method is not necessarily the steps of the method or It should also be understood that the operations are not limited to the order listed.

  In the claims and in the specification above, any transitional phrase such as “comprising”, “including”, “carrying”, “having” ) "," Containing "," involving "," holding "," composed of ", etc. are non-limiting Should be understood. In other words, it should be understood that the meaning includes, but is not limited to, those listed. Only the transitional phrases “consisting of” and “consisting essentially of” are described in the United States Patent Office Manual of Patent Exchanging Procedures, Section 2111.03. Each is a limited or semi-limiting transitional phrase.

Claims (83)

A spray dryer for use in drying a fluid,
An article comprising: a first microfluidic channel having an opening as a nozzle; and a second microfluidic channel intersecting the first microfluidic channel at an intersection upstream of the nozzle;
A spray dryer comprising a drying region for receiving the output from the nozzle.   The spray dryer of claim 1, wherein the article further comprises a first fluid source in fluid communication with the first microfluidic channel.   The spray dryer of claim 2, wherein the first fluid source comprises a water source that is immiscible with water.   The spray dryer of any one of claims 1 to 3, wherein the article further comprises a second fluid source in fluid communication with the second microfluidic channel.   The spray dryer of claim 4, wherein the second fluid source comprises a water source that is immiscible with water.   The article further comprises a third microfluidic channel in fluid communication with the second fluid source, wherein the third microfluidic channel is at the intersection of the first microfluidic channel upstream of the nozzle. 6. A spray dryer according to any one of claims 4 or 5, which intersects the fluid channel.   A fourth microfluidic channel that intersects the first microfluidic channel at a second intersection that is upstream of the intersection of the first microfluidic channel and the second microfluidic channel; The spray dryer according to any one of claims 1 to 6, further comprising:   The spray dryer of claim 7, wherein the article further comprises a third fluid source in fluid communication with the fourth microfluidic channel.   The spray dryer according to claim 8, wherein the third fluid source comprises an air source.   The article comprises a fifth microfluidic channel in fluid communication with the third fluid source, the fifth microfluidic channel intersecting the first microfluidic channel at the second intersection. The spray dryer according to claim 9.   The spray dryer according to claim 1, further comprising a heater for heating the drying region.   The spray dryer of claim 11, wherein the heater is capable of heating the drying zone to a temperature of at least about 40 degrees Celsius.   13. A spray dryer according to any one of claims 11 or 12, wherein the heater is capable of heating the drying zone to a temperature of at least about 60 ° C.   14. A spray dryer according to any one of the preceding claims, wherein the drying area is at least partially closed.   The spray dryer according to claim 1, wherein the drying region is included in a drying chamber.   16. A spray dryer according to any one of the preceding claims, wherein the first microfluidic channel has an average cross-sectional dimension of less than about 1 mm.   17. A spray dryer according to any one of the preceding claims, wherein the opening has a cross-sectional aspect ratio of at least about 3: 1.   18. A spray dryer according to any one of the preceding claims, wherein the opening has a cross-sectional aspect ratio of at least about 5: 1.   19. A spray dryer according to any one of the preceding claims, wherein the first microfluidic channel has a cross-sectional aspect ratio of at least about 5: 1.   20. A spray dryer according to any one of the preceding claims, wherein the article comprises an elastomeric polymer.   21. A spray dryer according to any one of the preceding claims, wherein the article consists essentially of an elastomeric polymer.   The spray dryer according to any one of claims 1 to 21, wherein the article comprises polydimethylsiloxane.   23. A spray dryer according to any one of the preceding claims, wherein the article is substantially planar.   The spray dryer according to any one of claims 1 to 23, wherein the article is mechanically deformable.   The spray dryer according to any one of claims 1 to 24, wherein the fluid channels in the article are arranged so as to be pseudo-two-dimensional.   26. A spray dryer according to any one of the preceding claims, wherein at least a portion of the first microfluidic channel is coated with a hydrophilic coating.   27. A spray dryer according to any one of the preceding claims, wherein at least a portion of the first microfluidic channel is hydrophilic.   An apparatus comprising at least 10 spray dryers according to any one of claims 1 to 27.   29. The apparatus of claim 28, wherein the at least 10 spray dryers can draw liquid from a common fluid source. A method of spray drying,
Providing a first liquid comprising a species dissolved in the first liquid;
Exposing the first liquid to the second liquid in a fluid channel for a period of about 30 seconds or less, wherein the species is not substantially soluble in the second liquid. When,
Spraying the first liquid and the second liquid onto a dry area outside the fluid channel.   32. The method of claim 30, wherein the first liquid and the second liquid are immiscible.   32. A method according to any one of claims 30 or 31, wherein the first liquid is miscible with water.   33. A method according to any one of claims 30 to 32, wherein the first liquid comprises isopropyl alcohol.   34. A method according to any one of claims 30 to 33, wherein the second liquid is miscible with water.   35. A method according to any one of claims 30 to 34, wherein the second liquid comprises water.   36. A method according to any one of claims 30 to 35, further comprising heating the dry zone to a temperature of at least about 40C.   37. A method according to any one of claims 30 to 36, further comprising the step of at least partially enclosing the first liquid with the second liquid.   38. The method of claim 37, wherein the first fluid is surrounded by the second liquid such that the first liquid does not contact a wall of the fluid channel.   39. A method according to any one of claims 30 to 38, wherein the species precipitates when the first liquid is exposed to the second liquid.   40. A method according to any one of claims 30 to 39, wherein the fluid channel is a microfluidic channel.   41. A method according to any one of claims 30 to 40, wherein the fluid channel is defined within an article.   42. Exposing the first liquid and / or the second liquid to a gas and forming droplets in the dry region from the first liquid and the second liquid. The method of any one of these.   43. The method of claim 42, wherein the gas is air.   44. Exposing the first liquid and / or the second liquid to an electric field to form droplets in the dry region from the first liquid and the second liquid. The method of any one of these.   45. A method according to any one of claims 30 to 44, further comprising collecting particles comprising the species within the dry zone.   46. The method of claim 45, wherein the particles are substantially monodispersed.   47. The method of any one of claims 45 or 46, wherein the particles have an average cross-sectional dimension of less than about 20 micrometers.   48. The method of any one of claims 45 to 47, wherein the particles have an average cross-sectional dimension of less than about 15 micrometers.   49. A method according to any one of claims 45 to 48, wherein the particles have an average cross-sectional dimension of less than about 10 micrometers.   50. The method of any one of claims 45 to 49, wherein the particles have an average cross-sectional dimension of less than about 5 micrometers.   51. The method of any one of claims 45-50, wherein the particles have an average cross-sectional dimension of less than about 1 micrometer.   52. The method of any one of claims 45 to 51, wherein the particles have an average cross-sectional dimension of less than about 300 nm.   53. A method according to any one of claims 45 to 52, wherein the particles have an average cross-sectional dimension of less than about 100 nm.   54. The method of any one of claims 45 to 53, wherein at least a portion of the species within the particle is not crystalline.   55. The method of any one of claims 45-54, further comprising producing about 10 g or less of the particles.   56. The method of any one of claims 45 to 55, further comprising producing about 3g or less of the particles.   57. The method of any one of claims 45 to 56, further comprising producing about 1 g or less of the particles.   58. A method according to any one of claims 45 to 57, wherein the particles are produced by drying the first liquid and / or the second liquid in the drying zone.   59. A method according to any one of claims 45 to 58, further comprising collecting at least a portion of the particles in a collection chamber having a volume of less than about 20 ml.   60. The method of any one of claims 30-59, wherein the species has a molecular weight of less than about 1000 Da.   61. A method according to any one of claims 30 to 60, wherein the species is a pharmaceutical agent.   62. A method according to any one of claims 30 to 61, wherein the species is danazol.   63. A method according to any one of claims 30 to 62, wherein the first liquid flows in layers through the fluid channel.   64. The method of any one of claims 30 to 63, wherein the second liquid flows in layers through the fluid channel.   65. The method of any one of claims 30 to 64, wherein the first liquid and / or the second liquid comprises the species of crystallization inhibitor.   66. The method of claim 65, wherein the crystallization inhibitor is poly (vinyl pyrrolidone).   67. A method according to any one of claims 30 to 66, comprising exposing the first liquid to the second liquid in the fluid channel for a time of 1 second or less.   68. The method of claim 67, wherein the time is about 15 seconds or less.   69. The method of any one of claims 67 or 68, wherein the time is about 10 seconds or less.   70. A method according to any one of claims 67 to 69, wherein the time is about 5 seconds or less.   71. The method of any one of claims 67 to 70, wherein the time is about 2 seconds or less.   72. A method according to any one of claims 30 to 71, wherein the dry region comprises a carrier liquid and the first liquid and the second liquid enter the carrier liquid.   73. The method of claim 72, wherein the first liquid and the second liquid form solid particles before entering the carrier liquid.   73. The method of claim 72, wherein the first liquid and the second liquid enter the carrier liquid in a liquid state. A spray dryer for use in drying a fluid,
An article comprising one or more microfluidic channels having both an average cross-sectional dimension of less than about 1 mm and an overall length of at least about 10 mm, wherein at least one of the microfluidic channels acts as a nozzle in the article An article having
A spray dryer comprising a drying region for receiving the output from the nozzle. A spray dryer for use in drying a fluid,
An article comprising a fluid channel having a cross-sectional aspect ratio of at least about 3: 1 and having an opening that acts as a nozzle;
A spray dryer comprising a drying region for receiving the output from the nozzle. A spray dryer for use in drying a fluid,
A fluid channel containing a first liquid and a second liquid;
An outlet of said fluid channel acting as a nozzle, wherein said second liquid is said first liquid so that said first liquid does not contact the wall of said fluid channel closest to said outlet Surrounding the liquid, the outlet,
And a drying area for receiving the output from the nozzle. A method of spray drying,
Exposing the first liquid to the second liquid in the microfluidic channel;
Draining the first liquid and the second liquid to a dry area outside the microfluidic channel.   When the first liquid comprises a first species, the second liquid comprises a second species, and the second species is exposed to the first species, the second species and the second species 79. The method of claim 78, wherein the one species precipitates together.   The first liquid includes a first species, the second liquid includes a second species, and the first species precipitates when the first species is exposed to the second species. 79. The method of claim 78. A method of spray drying a liquid, the method comprising:
Providing a fluid channel comprising a liquid, the liquid being delimited by a first bolus upstream of the liquid and delimited by a second bolus downstream of the liquid; Process,
Draining the liquid to a dry area outside the fluid channel. A method of spray drying,
Exposing the first liquid to the second liquid;
Draining the first liquid and the second liquid to a dry area outside the microfluidic channel to produce a product;
Collecting the product in a collection chamber having a volume of less than about 20 ml.   83. The method of claim 82, wherein the product comprises solid particles.

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